Solid forms comprising 3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, compositions comprising the same, and methods of using the same

ABSTRACT

Provided herein are solid forms comprising 3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. Pharmaceutical compositions comprising the solid forms and methods for treating, preventing and managing various disorders are also disclosed.

This application claims priority to U.S. Provisional Patent ApplicationNo. 60/995,675, filed Sep. 26, 2007, the content of which isincorporated by reference herein in its entirety.

1. FIELD

Provided herein are solid forms comprising3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.Pharmaceutical compositions comprising the solid forms and methods fortreating, preventing and managing various disorders are also disclosed.

2. BACKGROUND 2.1 Solid Forms of Pharmaceutical Compounds

The identification and selection of a solid form of a pharmaceuticalcompound is complex, given that a change in solid form may affect avariety of physical and chemical properties, which may provide benefitsor drawbacks in processing, formulation, stability and bioavailability,among other important pharmaceutical characteristics. Potentialpharmaceutical solids include crystalline solids and amorphous solids.Amorphous solids are characterized by a lack of long-range structuralorder, whereas crystalline solids are characterized by structuralperiodicity. The desired class of pharmaceutical solid depends upon thespecific application; amorphous solids are sometimes selected on thebasis of, e.g., an enhanced dissolution profile, while crystallinesolids may be desirable for properties such as, e.g., physical orchemical stability (see, e.g., S. R. Vippagunta et al., Adv. Drug.Deliv. Rev., (2001) 48:3-26; L. Yu, Adv. Drug. Deliv. Rev., (2001)48:27-42).

Whether crystalline or amorphous, potential solid forms of apharmaceutical compound include single-component and multiple-componentsolids. Single-component solids consist essentially of thepharmaceutical compound in the absence of other compounds. Variety amongsingle-component crystalline materials may potentially arise from thephenomenon of polymorphism, wherein multiple three-dimensionalarrangements exist for a particular pharmaceutical compound (see, e.g.,S. R. Byrn et al., Solid State Chemistry of Drugs, (1999) SSCI, WestLafayette). The importance of discovering polymorphs was underscored bythe case of Ritonavir, an HIV protease inhibitor that was formulated assoft gelatin capsules. About two years after the product was launched,the unanticipated precipitation of a new, less soluble polymorph in theformulation necessitated the withdrawal of the product from the marketuntil a more consistent formulation could be developed (see S. R.Chemburkar et al., Org. Process Res. Dev., (2000) 4:413-417).

Additional diversity among the potential solid forms of a pharmaceuticalcompound may arise from the possibility of multiple-component solids.Crystalline solids comprising two or more ionic species are termed salts(see, e.g., Handbook of Pharmaceutical Salts Properties, Selection andUse, P. H. Stahl and C. G. Wermuth, Eds., (2002), Wiley, Weinheim).Additional types of multiple-component solids that may potentially offerother property improvements for a pharmaceutical compound or saltthereof include, e.g., hydrates, solvates, co-crystals and clathrates,among others (see, e.g., S. R. Byrn et al., Solid State Chemistry ofDrugs, (1999) SSCI, West Lafayette). Moreover, multiple-componentcrystal forms may potentially be susceptible to polymorphism, wherein agiven multiple-component composition may exist in more than onethree-dimensional crystalline arrangement.

The variety of possible solid forms creates potential diversity inphysical and chemical properties for a given pharmaceutical compound.The discovery and selection of solid forms is of great importance in thedevelopment of an effective, stable and marketable pharmaceuticalproduct.

2.2 Pathobiology of Cancer and Other Diseases

Cancer is characterized primarily by an increase in the number ofabnormal cells derived from a given normal tissue, invasion of adjacenttissues by these abnormal cells, or lymphatic or blood-borne spread ofmalignant cells to regional lymph nodes and to distant sites(metastasis). Clinical data and molecular biologic studies indicate thatcancer is a multistep process that begins with minor preneoplasticchanges, which may under certain conditions progress to neoplasia. Theneoplastic lesion may evolve clonally and develop an increasing capacityfor invasion, growth, metastasis, and heterogeneity, especially underconditions in which the neoplastic cells escape the host's immunesurveillance. (Roitt, I., Brostoff, J and Kale, D., Immunology,17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993)).

There is an enormous variety of cancers which are described in detail inthe medical literature. Examples includes cancer of the lung, colon,rectum, prostate, breast, brain, and intestine. The incidence of cancercontinues to climb as the general population ages, as new cancersdevelop, and as susceptible populations (e.g., people infected with AIDSor excessively exposed to sunlight) grow. However, options for thetreatment of cancer are limited. For example, in the case of bloodcancers (e.g., multiple myeloma), few treatment options are available,especially when conventional chemotherapy fails and bone-marrowtransplantation is not an option. A tremendous demand therefore existsfor new methods and compositions that can be used to treat patients withcancer.

Many types of cancers are associated with new blood vessel formation, aprocess known as angiogenesis. Several of the mechanisms involved intumor-induced angiogenesis have been elucidated. The most direct ofthese mechanisms is the secretion by the tumor cells of cytokines withangiogenic properties. Examples of these cytokines include acidic andbasic fibroblastic growth factor (a,b-FGF), angiogenin, vascularendothelial growth factor (VEGF), and TNF-α. Alternatively, tumor cellscan release angiogenic peptides through the production of proteases andthe subsequent breakdown of the extracellular matrix where somecytokines are stored (e.g., b-FGF). Angiogenesis can also be inducedindirectly through the recruitment of inflammatory cells (particularlymacrophages) and their subsequent release of angiogenic cytokines (e.g.,TNF-α, b-FGF).

A variety of other diseases and disorders are also associated with, orcharacterized by, undesired angiogenesis. For example, enhanced orunregulated angiogenesis has been implicated in a number of diseases andmedical conditions including, but not limited to, ocular neovasculardiseases, choroidal neovascular diseases, retina neovascular diseases,rubeosis (neovascularization of the angle), viral diseases, geneticdiseases, inflammatory diseases, allergic diseases, and autoimmunediseases. Examples of such diseases and conditions include, but are notlimited to: diabetic retinopathy; retinopathy of prematurity; cornealgraft rejection; neovascular glaucoma; retrolental fibroplasia;arthritis; and proliferative vitreoretinopathy.

Accordingly, compounds that can control angiogenesis or inhibit theproduction of certain cytokines, including TNF-α, may be useful in thetreatment and prevention of various diseases and conditions.

2.3 Treating Cancer

Current cancer therapy may involve surgery, chemotherapy, hormonaltherapy and/or radiation treatment to eradicate neoplastic cells in apatient (see, e.g., Stockdale, 1998, Medicine, vol. 3, Rubenstein andFederman, eds., Chapter 12, Section IV). Recently, cancer therapy couldalso involve biological therapy or immunotherapy. All of theseapproaches pose significant drawbacks for the patient. Surgery, forexample, may be contraindicated due to the health of a patient or may beunacceptable to the patient.

Additionally, surgery may not completely remove neoplastic tissue.Radiation therapy is only effective when the neoplastic tissue exhibitsa higher sensitivity to radiation than normal tissue. Radiation therapycan also often elicit serious side effects. Hormonal therapy is rarelygiven as a single agent. Although hormonal therapy can be effective, itis often used to prevent or delay recurrence of cancer after othertreatments have removed the majority of cancer cells. Biologicaltherapies and immunotherapies are limited in number and may produce sideeffects such as rashes or swellings, flu-like symptoms, including fever,chills and fatigue, digestive tract problems or allergic reactions.

With respect to chemotherapy, there are a variety of chemotherapeuticagents available for treatment of cancer. A majority of cancerchemotherapeutics act by inhibiting DNA synthesis, either directly, orindirectly by inhibiting the biosynthesis of deoxyribonucleotidetriphosphate precursors, to prevent DNA replication and concomitant celldivision. Gilman et al., Goodman and Gilman's: The Pharmacological Basisof Therapeutics, Tenth Ed. (McGraw Hill, New York).

Despite availability of a variety of chemotherapeutic agents,chemotherapy has many drawbacks. Stockdale, Medicine, vol. 3, Rubensteinand Federman, eds., ch. 12, sect. 10, 1998. Almost all chemotherapeuticagents are toxic, and chemotherapy causes significant, and oftendangerous side effects including severe nausea, bone marrow depression,and immunosuppression. Additionally, even with administration ofcombinations of chemotherapeutic agents, many tumor cells are resistantor develop resistance to the chemotherapeutic agents. In fact, thosecells resistant to the particular chemotherapeutic agents used in thetreatment protocol often prove to be resistant to other drugs, even ifthose agents act by different mechanism from those of the drugs used inthe specific treatment. This phenomenon is referred to as pleiotropicdrug or multidrug resistance. Because of the drug resistance, manycancers prove or become refractory to standard chemotherapeutictreatment protocols.

Other diseases or conditions associated with, or characterized by,undesired angiogenesis are also difficult to treat. However, somecompounds such as protamine, hepain and steroids have been proposed tobe useful in the treatment of certain specific diseases. Taylor et al.,Nature 297:307 (1982); Folkman et al., Science 221:719 (1983); and U.S.Pat. Nos. 5,001,116 and 4,994,443.

Still, there is a significant need for effective methods of treating,preventing and managing cancer and other diseases and conditions,including for diseases that are refractory to standard treatments, suchas surgery, radiation therapy, chemotherapy and hormonal therapy, whilereducing or avoiding the toxicities and/or side effects associated withthe conventional therapies.

Accordingly, provided herein are embodiments addressing the need forsolid forms comprising the compound chemically named3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, whichwas disclosed in U.S. Patent Application Publication No. US2008/0161328, which published on Jul. 3, 2008. Provided herein areembodiments in which certain novel solid forms include particularadvantageous physical properties making them useful, e.g., formanufacturing, processing, formulation and/or storage, while alsopossessing particularly advantageous biological properties, such asbioavailability and biological activity.

3. SUMMARY

Provided herein are novel solid forms of3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione,pharmaceutically acceptable salts, solvates (e.g., hydrates), prodrugs,clathrates, or stereoisomers thereof.

Also provided are methods of treating and managing various diseases ordisorders. The methods comprise administering to a patient in need ofsuch treatment or management a therapeutically effective amount of asolid form provided herein.

Also provided herein are methods of preventing various diseases anddisorders, which comprise administering to a patient in need of suchprevention a prophylactically effective amount of a solid form providedherein.

Also provided herein are pharmaceutical compositions, single unit dosageforms, dosing regimens and kits which comprise a solid form providedherein.

4. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a representative XRPD pattern of the Form A crystal formof 3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 2 provides a photomicrograph depicting representative crystals ofthe Form A crystal form of3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 3 provides a representative TGA thermogram of the Form A crystalform of 3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 4 provides a representative DSC thermogram of the Form A crystalform of 3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 5 provides a representative DVS profile of the Form A crystal formof 3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 6 provides a representative XRPD pattern of the Form B crystal formof 3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 7 provides a photomicrograph depicting representative crystals ofthe Form B crystal form of3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 8 provides a representative TGA thermogram of the Form B crystalform of 3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 9 provides a representative DSC thermogram of the Form B crystalform of 3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

FIG. 10 provides a representative DVS profile of the Form B crystal formof 3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

5. DETAILED DESCRIPTION 5.1 Definitions

As used herein, the compound referred to by the chemical name3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionecorresponds to the chemical structure (I), depicted infra. In certainembodiments, the chemical name3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione is usedto refer to its free base form or its ionized forms, which haveundergone salt formation such that the molecule is protonated at one ormore basic centers. To the extent that there is a discrepancy between achemical name of a compound and a depicted chemical structure of acompound provided herein, the chemical structure shall control.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts prepared from pharmaceutically acceptable, relatively non-toxicacids, including inorganic acids and organic acids. Suitable acidsinclude, but are not limited to, acetic, benzenesulfonic, benzoic,camphorsulfonic, carbonic, citric, dihydrogenphosphoric, ethenesulfonic,fumaric, galactunoric, gluconic, glucuronic, glutamic, hydrobromic,hydrochloric, hydriodic, isobutyric, isethionic, lactic, maleic, malic,malonic, mandelic, methanesulfonic, monohydrogencarbonic,monohydrogenphosphoric, monohydrogensulfuric, mucic, nitric, pamoic,pantothenic, phosphoric, phthalic, propionic, suberic, succinic,sulfuric, tartaric, toluenesulfonic, including p-toluenesulfonictoluenesulfonic m-toluenesulfonic and o-toluenesulfonic acids, and thelike (see, e.g., S. M. Berge et al., J. Pharm. Sci., 66:1-19 (1977); andHandbook of Pharmaceutical Salts: Properties, Selection and Use, P. H.Stahl and C. G. Wermuth, Eds., (2002), Wiley, Weinheim). Also includedare salts of other relatively non-toxic compounds that possess acidiccharacter, including amino acids, such as aspartic acid and the like,and other compounds, such as aspirin, ibuprofen, saccharin, and thelike. Acid addition salts can be obtained by contacting the neutral formof such compounds with a sufficient amount of the desired acid, eitherneat or in a suitable solvent. As solids, salts can exist in crystallineor amorphous modifications.

The terms “solid form,” “solid forms” and related terms, when usedherein to refer to3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, refer toa physical form comprising3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione which isnot predominantly in a liquid or a gaseous state. Solid forms may becrystalline, amorphous, partially crystalline or partially amorphous.

The term “crystalline” and related terms used herein, when used todescribe a substance, component, product, or form, means that thesubstance, component or product is substantially crystalline asdetermined by X-ray diffraction. (See, e.g., Remington's PharmaceuticalSciences, 18^(th) ed., Mack Publishing, Easton Pa., 173 (1990); TheUnited States Pharmacopeia, 23^(rd) ed., 1843-1844 (1995)).

The term “crystal forms” and related terms herein refers to the variouscrystalline modifications comprising a given substance, includingsingle-component crystal forms and multiple-component crystal forms, andincluding, but not limited to, polymorphs, solvates, hydrates, and othermolecular complexes, as well as salts, solvates of salts, hydrates ofsalts, other molecular complexes of salts, and polymorphs thereof. Incertain embodiments, a crystal form of a substance may be substantiallyfree of amorphous forms and/or other crystal forms. In otherembodiments, a crystal form of a substance may contain less than about1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of oneor more amorphous forms and/or other crystal forms on a weight basis.Crystal forms of a substance can be obtained by a number of methods, asknown in the art. Such methods include, but are not limited to, meltrecrystallization, melt cooling, solvent recrystallization,recrystallization in confined spaces such as, e.g., in nanopores orcapillaries, recrystallization on surfaces or templates such as, e.g.,on polymers, recrystallization in the presence of additives, such as,e.g., co-crystal counter-molecules, desolvation, dehydration, rapidevaporation, rapid cooling, slow cooling, vapor diffusion, sublimation,grinding and solvent-drop grinding.

The terms “polymorphs,” “polymorphic forms” and related terms hereinrefer to two or more crystal forms that consist essentially of the samemolecule, molecules or ions. Different polymorphs may have differentphysical properties such as, for example, melting temperatures, heats offusion, solubilities, dissolution rates and/or vibrational spectra as aresult of the arrangement or conformation of the molecules or ions inthe crystal lattice. The differences in physical properties exhibited bypolymorphs may affect pharmaceutical parameters such as storagestability, compressibility and density (important in formulation andproduct manufacturing), and dissolution rate (an important factor inbioavailability). Differences in stability can result from changes inchemical reactivity (e.g., differential oxidation, such that a dosageform discolors more rapidly when comprised of one polymorph than whencomprised of another polymorph) or mechanical changes (e.g., tabletscrumble on storage as a kinetically favored polymorph converts tothermodynamically more stable polymorph) or both (e.g., tablets of onepolymorph are more susceptible to breakdown at high humidity). As aresult of solubility/dissolution differences, in the extreme case, somepolymorphic transitions may result in lack of potency or, at the otherextreme, toxicity. In addition, the physical properties of the crystalmay be important in processing; for example, one polymorph might be morelikely to form solvates or might be difficult to filter and wash free ofimpurities (e.g., particle shape and size distribution might bedifferent between polymorphs).

The terms “solvate” and “solvated,” as used herein, refer to a crystalform of a substance which contains solvent. The terms “hydrate” and“hydrated” refer to a solvate wherein the solvent is water. “Polymorphsof solvates” refer to the existence of more than one crystal form for aparticular solvate composition. Similarly, “polymorphs of hydrates”refer to the existence of more than one crystal form for a particularhydrate composition. The term “desolvated solvate,” as used herein,refers to a crystal form of a substance which can only be made byremoving the solvent from a solvate.

The term “amorphous,” “amorphous form,” and related terms used hereinmean that the substance, component or product in question is notsubstantially crystalline as determined by X-ray diffraction. In certainembodiments, an amorphous form of a substance may be substantially freeof other amorphous forms and/or crystal forms. In other embodiments, anamorphous form of a substance may contain less than about 1%, 2%, 3%,4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of one or moreother amorphous forms and/or crystal forms on a weight basis. Amorphousforms of a substance can be obtained by a number of methods, as known inthe art. Such methods include, but are not limited to, heating, meltcooling, rapid melt cooling, solvent evaporation, rapid solventevaporation, desolvation, sublimation, grinding, cryo-grinding andfreeze drying.

As used herein, and unless otherwise specified, the terms “about” and“approximately,” when used in connection with doses, amounts, or weightpercent of ingredients of a composition or a dosage form, mean a dose,amount, or weight percent that is recognized by one of ordinary skill inthe art to provide a pharmacological effect equivalent to that obtainedfrom the specified dose, amount, or weight percent. Specifically, theterms “about” and “approximately,” when used in this context,contemplate a dose, amount, or weight percent within 15%, morespecifically within 10%, more specifically within 5%, of the specifieddose, amount, or weight percent.

Techniques for characterizing crystal forms and amorphous forms include,but are not limited to, thermal gravimetric analysis (TGA), differentialscanning calorimetry (DSC), X-ray powder diffractometry (XRPD),single-crystal X-ray diffractometry, vibrational spectroscopy, e.g.,infrared (IR) and Raman spectroscopy, solid-state and solution nuclearmagnetic resonance (NMR) spectroscopy, optical microscopy, hot stageoptical microscopy, scanning electron microscopy (SEM), electroncrystallography and quantitative analysis, particle size analysis (PSA),surface area analysis, solubility studies and dissolution studies.

As used herein, and unless otherwise specified, the terms “about” and“approximately,” when used in connection with a numeric value or rangeof values which is provided to characterize a particular solid form,e.g., a specific temperature or temperature range, such as, for example,that describing a melting, dehydration, desolvation or glass transitiontemperature; a mass change, such as, for example, a mass change as afunction of temperature or humidity; a solvent or water content, interms of, for example, mass or a percentage; or a peak position, suchas, for example, in analysis by IR or Raman spectroscopy or XRPD;indicate that the value or range of values may deviate to an extentdeemed reasonable to one of ordinary skill in the art while stilldescribing the particular solid form. Specifically, the terms “about”and “approximately,” when used in this context, indicate that thenumeric value or range of values may vary within 20%, 10%, 9%, 8%, 7%,6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value orrange of values. In particular embodiments, the locations of XRPD peakpositions may vary by up to ±0.2 degrees two theta.

As used herein, a crystalline or amorphous form that is “pure,” i.e.,substantially free of other crystalline or amorphous forms, containsless than about 10 percent by weight of one or more other crystalline oramorphous form, preferably less than about 5 percent by weight of one ormore other crystalline or amorphous form, more preferably less thanabout 3 percent by weight of one or more other crystalline or amorphousform, most preferably less than about 1 percent by weight of one or moreother crystalline or amorphous form.

As used herein, a solid form that is “substantially physically pure” issubstantially free from other solid forms. In certain embodiments, acrystal form that is substantially physically pure contains less thanabout 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05% or 0.01% of one ormore other solid forms. The detection of other solid forms can beaccomplished by any method apparent to a person of ordinary skill in theart, including, but not limited to, diffraction analysis, thermalanalysis, elemental combustion analysis and/or spectroscopic analysis.

As used herein, a solid form that is “substantially chemically pure” issubstantially free from other chemical compounds. In certainembodiments, a solid form that is substantially chemically pure containsless than about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%,6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05% or 0.01% ofone or more other chemical compounds. The detection of other chemicalcompounds can be accomplished by any method apparent to a person ofordinary skill in the art, including, but not limited to, methods ofchemical analysis, such as, e.g., mass spectrometry analysis,spectroscopic analysis, thermal analysis, elemental combustion analysisand/or chromatographic analysis.

As used herein and unless otherwise indicated, a chemical compound,solid form or composition that is “substantially free” of a chemicalcompound or solid form means that the compound, solid form orcomposition contains, in certain embodiments, less than about 50%, 45%,40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%,0.5%, 0.4%, 0.3%, 0.2% 0.1%, 0.05% or 0.01% by weight of the compound,solid form or composition.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” refer to the eradication or amelioration of adisease or disorder, or of one or more symptoms associated with thedisease or disorder. In certain embodiments, the terms refer tominimizing the spread or worsening of the disease or disorder resultingfrom the administration of one or more prophylactic or therapeuticagents to a subject with such a disease or disorder. In someembodiments, the terms refer to the administration of a compoundprovided herein, with or without other additional active agent, afterthe onset of symptoms of the particular disease.

As used herein, and unless otherwise specified, the terms “prevent,”“preventing” and “prevention” refer to the prevention of the onset,recurrence or spread of a disease or disorder, or of one or moresymptoms thereof. In certain embodiments, the terms refer to thetreatment with or administration of a compound provided herein, with orwithout other additional active compound, prior to the onset ofsymptoms, particularly to patients at risk of disease or disordersprovided herein. The terms encompass the inhibition or reduction of asymptom of the particular disease. Patients with familial history of adisease in particular are candidates for preventive regimens in certainembodiments. In addition, patients who have a history of reoccurringsymptoms are also potential candidates for the prevention. In thisregard, the term “prevention” may be interchangeably used with the term“prophylactic treatment.”

As used herein, and unless otherwise specified, the terms “manage,”“managing” and “management” refer to preventing or slowing theprogression, spread or worsening of a disease or disorder, or of one ormore symptoms thereof. Often, the beneficial effects that a subjectderives from a prophylactic and/or therapeutic agent do not result in acure of the disease or disorder. In this regard, the term “managing”encompasses treating a patient who had suffered from the particulardisease in an attempt to prevent or minimize the recurrence of thedisease.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment or management of a disease ordisorder, or to delay or minimize one or more symptoms associated withthe disease or disorder. A therapeutically effective amount of acompound means an amount of therapeutic agent, alone or in combinationwith other therapies, which provides a therapeutic benefit in thetreatment or management of the disease or disorder. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease ordisorder, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease or disorder, or prevent its recurrence. A prophylacticallyeffective amount of a compound means an amount of therapeutic agent,alone or in combination with other agents, which provides a prophylacticbenefit in the prevention of the disease. The term “prophylacticallyeffective amount” can encompass an amount that improves overallprophylaxis or enhances the prophylactic efficacy of anotherprophylactic agent.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients (and in the specified amounts, ifindicated), as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts. By “pharmaceutically acceptable” it is meant thediluent, excipient or carrier must be compatible with the otheringredients of the formulation and not deleterious to the recipientthereof.

The term “therapeutically and prophylactically effective amount” refersto the amount of the subject solid form that will elicit the biologicalor medical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician or that is sufficient to prevent development of or alleviateto some extent one or more of the symptoms of the disease being treated.

The term “subject” is defined herein to include animals such as mammals,including, but not limited to, primates (e.g., humans), cows, sheep,goats, horses, dogs, cats, rabbits, rats, mice and the like. In specificembodiments, the subject is a human.

In addition to solid forms of3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, providedherein are solid forms of prodrugs of3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. Prodrugsof the compounds described herein are structurally modified forms of thecompound that readily undergo chemical changes under physiologicalconditions to provide the compound. Additionally, prodrugs can beconverted to the compound by chemical or biochemical methods in an exvivo environment. For example, prodrugs can be slowly converted to acompound when placed in a transdermal patch reservoir with a suitableenzyme or chemical reagent. Prodrugs are often useful because, in somesituations, they may be easier to administer than the compound, orparent drug. They may, for instance, be bioavailable by oraladministration whereas the parent drug is not. The prodrug may also haveimproved solubility in pharmaceutical compositions over the parent drug.A wide variety of prodrug derivatives are known in the art, such asthose that rely on hydrolytic cleavage or oxidative activation of theprodrug. An example, without limitation, of a prodrug would be acompound which is administered as an ester (the “prodrug”), but then ismetabolically hydrolyzed to the carboxylic acid, the active entity.Additional examples include petidyl derivatives of a compound.

The compounds provide herein may also contain unnatural proportions ofatomic isotopes at one or more of the atoms. For example, the compoundmay be radiolabeled with radioactive isotopes, such as for exampletritium (³H), iodine-125 (¹²⁵I) sulfur-35 (³⁵S), or carbon-14 (¹⁴C).Radiolabeled compounds are useful as therapeutic agents, e.g., cancertherapeutic agents, research reagents, e.g., binding assay reagents, anddiagnostic agents, e.g., in vivo imaging agents. All isotopic variationsof the compounds provided herein, whether radioactive or not, areintended to be encompassed herein.

5.2 Solid Forms Comprising3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione

Provided herein are single-component and multiple-component solid formscomprising3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione can besynthesized or obtained according to any method apparent to those ofskill in the art based upon the teachings herein, including the methodsdescribed in detail in the examples below.3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione can alsobe prepared according to the methods described in U.S. PatentApplication Publication No. US 2008/0161328, published Jul. 3, 2008,which claims priority to U.S. Provisional Patent Application No.60/847,471, filed Sep. 26, 2006, the entirety of each of which isincorporated by reference herein.

Solid forms comprising3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione includesingle-component and multiple-component forms, including crystal formscomprising3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione andamorphous forms comprising3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, andincluding, but not limited to, polymorphs, salts, solvates, hydrates,co-crystals and clathrates comprising3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. Solidforms provided herein can be prepared by the methods described herein,or by techniques known in the art, including, but not limited to,heating, cooling, freeze drying, lyophilization, quench cooling themelt, rapid solvent evaporation, slow solvent evaporation, solventrecrystallization, antisolvent addition, slurry recrystallization,crystallization from the melt, desolvation, recrystallization inconfined spaces such as, e.g., in nanopores or capillaries,recrystallization on surfaces or templates such as, e.g., on polymers,recrystallization in the presence of additives, such as, e.g.,co-crystal counter-molecules, desolvation, dehydration, rapid cooling,slow cooling, exposure to solvent and/or water, drying, including, e.g.,vacuum drying, vapor diffusion, sublimation, grinding (including, e.g.,cryo-grinding and solvent-drop grinding), microwave-inducedprecipitation, sonication-induced precipitation, laser-inducedprecipitation and precipitation from a supercritical fluid. The particlesize of the resulting solid forms, which can vary, (e.g., from nanometerdimensions to millimeter dimensions), can be controlled, e.g., byvarying crystallization conditions, such as, e.g., the rate ofcrystallization and/or the crystallization solvent system, or byparticle-size reduction techniques, e.g., grinding, milling, micronizingor sonication.

Provided herein are compositions comprising one or more of the solidforms. Also provided herein are compositions of one or more solid formsin combination with other active ingredients. Also provided herein aremethods of using these compositions in the treatment, prevention ormanagement of conditions and disorders including, but not limited to,cancer, a cardiovascular disease, a renal disease, an autoimmunecondition, an inflammatory condition, macular degeneration,ischemia-reperfusion injury, pain and related syndromes, disease-relatedwasting, an asbestos-related condition, pulmonary hypertension, centralnervous system (CNS) injury/damage or a condition treatable orpreventable by inhibition of a kinase pathway.

While not intending to be bound by any particular theory, certain solidforms provided herein are characterized by physical properties, e.g.,stability, solubility and dissolution rate, appropriate for clinical andtherapeutic dosage forms. Moreover, while not wishing to be bound by anyparticular theory, certain salts and crystal forms provided herein arecharacterized by physical properties, e.g., crystal morphology,compressibility and hardness, suitable for manufacture of a solid dosageform. Such properties can be determined using techniques such as X-raydiffraction, microscopy, IR spectroscopy and thermal analysis, asdescribed herein and known in the art.

5.2.1 Form A of3-(2,5-dimethyl-4-oxo-4H-(quinazolin-3-yl)-piperidine-2,6-dione

Certain embodiments herein provide a solid form comprising3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione,designated herein as Form A. In certain embodiments, Form A can beobtained from various aqueous and/or organic solvent systems, including,but not limited to, solvent systems comprising one or more of thefollowing solvents or solvent combinations: acetone, acetonitrile,n-butanol, ethanol, ethyl acetate, heptane, methanol, methylenechloride, methyl ethyl ketone, methyl t-butyl ether, 2-propanol,toluene, tetrahydrofuran, N-methylpyrrolidone/ethanol,dimethylsulfoxide/ethanol and dimethylformamide/ethanol. In certainembodiments, Form A can be obtained by drying (e.g., vacuum drying)another solid form comprising3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (e.g.,Form B).

In certain embodiments, Form A is substantially crystalline, asindicated by, e.g., X-ray powder diffraction measurements. Arepresentative XRPD pattern of Form A is provided in FIG. 1. In certainembodiments, Form A is characterized by XRPD peaks located at one ormore of the following approximate positions: 9.8; 12.1; 13.7; 15.1;17.4; 21.5; 21.8; 26.3; 27.5; and 32.5 degrees 2θ.

A photomicrograph depicting certain Form A crystals is provided in FIG.2. In certain embodiments, Form A crystals have a morphologysubstantially similar to that of the crystals depicted in FIG. 2. Incertain embodiments, Form A crystals are of approximately the same sizeas the crystals depicted in FIG. 2.

Representative thermal characteristics of Form A are shown in FIGS. 3and 4. A representative DSC thermogram of Form A is presented in FIG. 4.In certain embodiments, Form A exhibits a DSC thermogram comprising anendothermic event with an onset temperature at about 292° C. when heatedfrom approximately 25° C. to approximately 300° C. A representative TGAthermogram of Form A is presented in FIG. 3. In certain embodiments,Form A exhibits a mass loss of less than about 1% of the total mass ofthe sample between the temperatures of approximately 25° C. toapproximately 220° C. when heated from approximately 25° C. toapproximately 300° C. The thermal data indicate that Form A does notcontain substantial amounts of solvent (e.g., water) in the crystallattice.

In certain embodiments, Form A is substantially free of solvent andwater in the crystal lattice, as determined, e.g., via thermal analysis(such as, e.g., TG Analysis, TG-IR analysis, or TG-MS analysis),titration analysis for water content (such as, e.g., via volumetric orcoulometric Karl Fischer titration), spectroscopic analysis (such as,e.g., NMR), elemental analysis (such as, e.g., combustion analysis), orcrystal structure analysis (such as, e.g., single-crystal X-raydiffraction). In certain embodiments, Form A is an anhydrous crystalform comprising3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.

Without being limited by a particular theory, Form A exhibits desirablecharacteristics, e.g., for the synthesis, processing and manufacture ofdrug product comprising3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. Forexample, Form A has advantageous stability with respect to humidity,which is an important characteristic, e.g., for processing,manufacturing and storage considerations. As illustrated in FIG. 5, whensubjected to an isothermic (approximately 23.3° C.) moisture sorptiontest comprising an increase in relative humidity (RH) from approximately0% RH to approximately 50% RH, Form A exhibits a mass increase ofapproximately 1% relative to the ingoing dry mass. Moreover, whensubjected to an isothermic (approximately 23.3° C.) moisture sorptiontest comprising an increase in relative humidity (RH) from approximately0% RH to approximately 95% RH, Form A exhibits a total mass increase ofapproximately 4% relative to the ingoing mass. Moreover, when furtheranalyzed by decreasing the relative humidity from approximately 95% RHto approximately 0% RH, Form A loses approximately all of the adsorbedmoisture, thereby demonstrating a reversible mass gain upon exposure tomoisture. Thus, in certain embodiments, Form A is substantiallynon-hygroscopic. In certain embodiments, Form A exhibits a moisturesorption isotherm comprising a total mass increase of approximately 1%of the total mass of the sample when subjected to moisture sorptionanalysis from about 0% RH to about 50% RH at about 23.3° C. In certainembodiments, Form A exhibits a moisture sorption isotherm comprising atotal mass increase of approximately 4% of the total mass of the samplewhen subjected to moisture sorption analysis from about 0% RH to about95% RH at about 23.3° C.

Moreover, without being limited by a particular theory, Form A has anadvantageous physical stability profile, which is an importantcharacteristic, e.g., for processing and manufacturing considerations.For example, Form A is physically stable upon exposure to a 40° C., 75%RH environment for four weeks, as observed, e.g., by X-ray powderdiffraction measurements. Thus, in certain embodiments, Form A isphysically stable with respect to heat and/or humidity. Moreover, incertain embodiments, Form A does not exhibit physical transformationupon exposure to an environment of about 40° C. and about 75% RH forfour weeks.

Without being limited by a particular theory, Form A is physicallystable upon compression, which is an important characteristic, e.g., forformulation considerations. For example, Form A is physically stableupon compression testing comprising application of about 2,000 psipressure for about 1 minute, as observed, e.g., by X-ray powderdiffraction measurements. Thus, in certain embodiments, Form A isphysically stable with respect to compression. Moreover, in certainembodiments, Form A does not exhibit physical transformation uponexposure to about 2,000 psi pressure for about 1 minute.

In certain embodiments, Form A is substantially physically pure. Forexample, in certain embodiments, Form A is substantially free from othersolid forms, including other solid forms comprising3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, asdetermined, e.g., using methods of solid-state analysis including, butnot limited to, diffraction analysis, thermal analysis, elementalcombustion analysis and/or spectroscopic analysis. In certainembodiments, Form A is substantially chemically pure. For example, incertain embodiments, Form A is free from other chemical compounds, asdetermined, e.g., using methods of chemical analysis including, but notlimited to, mass spectrometry analysis, spectroscopic analysis, thermalanalysis, elemental combustion analysis and/or chromatographic analysis.In certain embodiments, Form A is substantially chemically pure andsubstantially physically pure.

5.2.2 Form B of3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione

Certain embodiments herein provide a solid form comprising3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione,designated herein as Form B. In certain embodiments, Form B can beobtained from various aqueous and/or organic solvent systems, including,but not limited to, solvent systems comprising one or more of thefollowing solvent or solvent mixtures: water, dimethylsulfoxide/water,ethanol/water, ethyl acetate, heptane, methylene chloride, methylt-butyl ether, toluene, N-methylpyrrolidone/water, anddimethylformamide/water. In certain embodiments, Form B can be obtainedby contacting another solid form comprising3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (e.g.,Form A) with water (e.g., liquid water or water vapor).

In certain embodiments, Form B contains approximately one molarequivalent of water in the crystal lattice per mole of3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, asdetermined, e.g., via thermal analysis (such as, e.g., TG Analysis,TG-IR analysis, or TG-MS analysis), titration analysis for water content(such as, e.g., via volumetric or coulometric Karl Fischer titration),spectroscopic analysis (such as, e.g., NMR), elemental analysis (suchas, e.g., combustion analysis), or crystal structure analysis (such as,e.g., single-crystal X-ray diffraction). In certain embodiments, Form Bis a monohydrate.

In certain embodiments, Form B is substantially crystalline, asindicated by, e.g., X-ray powder diffraction measurements. Arepresentative XRPD pattern of Form B is provided in FIG. 6. In certainembodiments, Form B is characterized by XRPD peaks located at one ormore of the following approximate positions: 9.1; 14.1; 15.1; 16.6;21.1; 21.8; 25.1; 28.7; and 35.4 degrees 2θ.

A photomicrograph depicting certain Form B crystals is provided in FIG.7. In certain embodiments, Form B crystals have a morphologysubstantially similar to that of the crystal depicted in FIG. 7. Incertain embodiments, Form B crystals are of approximately the same sizeas the crystals depicted in FIG. 7.

Representative thermal characteristics of Form B are shown in FIGS. 8and 9. A representative DSC thermogram of Form B is presented in FIG. 9.In certain embodiments, Form B exhibits a DSC thermogram comprising anendothermic event with a peak temperature at about 139° C. when heatedfrom approximately 25° C. to approximately 300° C. In certainembodiments, Form B exhibits a DSC thermogram comprising an endothermicevent with an onset temperature at about 290° C. when heated fromapproximately 25° C. to approximately 300° C. A representative TGAthermogram of Form B is presented in FIG. 8. In certain embodiments,Form B exhibits a TGA thermogram comprising a total mass loss ofapproximately 6% of the total mass of the sample between approximately25° C. and approximately 150° C. when heated from approximately 25° C.to approximately 275° C. The thermal data indicate that Form B containsa molar quantity of solvent in the crystal lattice corresponding toapproximately 1 mole of water per mole of3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. Thus, incertain embodiments, Form B loses about 6% of its total mass when heatedfrom about ambient temperature to about 150° C.

Without being limited by a particular theory, Form B exhibits desirablecharacteristics, e.g., for the synthesis, processing and manufacture ofdrug product comprising3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione. Forexample, Form B has an advantageous stability with respect to humidity,which is an important characteristic, e.g., for processing,manufacturing and storage considerations. As illustrated in FIG. 10,when subjected to an isothermic (approximately 23.3° C.) moisturesorption test comprising an increase in relative humidity (RH) fromapproximately 0% RH to approximately 50% RH, Form B exhibits a massincrease of approximately 1.5% relative to the ingoing mass. Moreover,when subjected to an isothermic (approximately 23.3° C.) moisturesorption test comprising an increase in relative humidity (RH) fromapproximately 0% RH to approximately 95% RH, Form B exhibits a totalmass increase of approximately 3% relative to the ingoing dry mass.Moreover, when further analyzing by decreasing the relative humidityfrom approximately 95% RH to approximately 0% RH, Form B losesapproximately all of the adsorbed moisture, thereby demonstrating areversible mass gain upon exposure to moisture. Thus, in certainembodiments, Form B is substantially non-hygroscopic. In certainembodiments, Form B exhibits a moisture sorption isotherm comprising atotal mass increase of approximately 1.5% of the total mass of thesample when subjected to moisture sorption analysis from about 0% RH toabout 50% RH at about 23.3° C. In certain embodiments, Form B exhibits amoisture sorption isotherm comprising a total mass increase ofapproximately 3% of the total mass of the sample when subjected tomoisture sorption analysis from about 0% RH to about 95% RH at about23.3° C.

Without being limited by a particular theory, Form B has an advantageousphysical stability profile, which an important characteristic, e.g., forprocessing and manufacturing considerations. For example, Form B isphysically stable upon exposure to a 40° C., 75% RH environment for fourweeks, as observed, e.g., by X-ray powder diffraction measurements.Thus, in certain embodiments, Form B is physically stable with respectto heat and/or humidity. Moreover, in certain embodiments, Form B doesnot exhibit physical transformation upon exposure to an environment of40° C. and 75% RH for four weeks.

Without being limited by a particular theory, Form B is physicallystable upon compression, which an important characteristic, e.g., forformulation considerations. For example, Form B is physically stableupon compression testing comprising application of about 2,000 psipressure for about 1 minute, as observed, e.g., by X-ray powderdiffraction measurements. Thus, in certain embodiments, Form B isphysically stable with respect to compression. Moreover, in certainembodiments, Form B does not exhibit physical transformation uponexposure to about 2,000 psi pressure for about 1 minute.

In certain embodiments, Form B is substantially physically pure. Forexample, in certain embodiments, Form B is substantially free from othersolid forms, including other solid forms comprising3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, asdetermined, e.g., using methods of solid-state analysis including, butnot limited to, diffraction analysis, thermal analysis, elementalcombustion analysis and/or spectroscopic analysis. In certainembodiments, Form B is substantially chemically pure. For example, incertain embodiments, Form B is free from other chemical compounds, asdetermined, e.g., using methods of chemical analysis including, but notlimited to, mass spectrometry analysis, spectroscopic analysis, thermalanalysis, elemental combustion analysis and/or chromatographic analysis.In certain embodiments, Form B is substantially chemically pure andsubstantially physically pure.

5.3 Methods of Treatment, Prevention and Management

Provided herein are methods of treating, preventing, and/or managingvarious diseases or disorders using a solid form provided herein. Incertain embodiments, provided are methods of treating, managing, andpreventing various diseases and disorders, which comprise administeringto a patient in need of such treatment, prevention or management atherapeutically or prophylactically effective amount of a solid formprovided herein. Examples of diseases and disorders are describedherein.

Examples of diseases or disorders include, but are not limited to,cancer, disorders associated with angiogenesis, pain including, but notlimited to, Complex Regional Pain Syndrome (“CPPS”), MacularDegeneration (“MD”) and related syndromes, skin diseases, pulmonarydisorders, asbestos-related disorders, parasitic diseases,immunodeficiency disorders, CNS disorders, CNS injury, atherosclerosisand related disorders, dysfunctional sleep and related disorders,hemoglobinopathy and related disorders (e.g., anemia), TNFα relateddisorders, and other various diseases and disorders.

Examples of cancer and precancerous conditions include, but are notlimited to, those described in U.S. Pat. Nos. 6,281,230 and 5,635,517 toMuller et al., in various U.S. patent publications to Zeldis, includingpublication nos. 2004/0220144A1, published Nov. 4, 2004 (Treatment ofMyelodysplastic Syndrome); 2004/0029832A1, published Feb. 12, 2004(Treatment of Various Types of Cancer); and 2004/0087546, published May6, 2004 (Treatment of Myeloproliferative Diseases). Examples alsoinclude those described in WO 2004/103274, published Dec. 2, 2004. Allof these references are incorporated herein in their entireties byreference.

Specific examples of cancer include, but are not limited to, cancers ofthe skin, such as melanoma; lymph node; breast; cervix; uterus;gastrointestinal tract; lung; ovary; prostate; colon; rectum; mouth;brain; head and neck; throat; testes; kidney; pancreas; bone; spleen;liver; bladder; larynx; nasal passages; and AIDS-related cancers. Thecompounds are also useful for treating cancers of the blood and bonemarrow, such as multiple myeloma and acute and chronic leukemias, forexample, lymphoblastic, myelogenous, lymphocytic, and myelocyticleukemias. The compounds provided herein can be used for treating,preventing or managing either primary or metastatic tumors.

Other specific cancers include, but are not limited to, advancedmalignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma,multiple brain metastase, glioblastoma multiforms, glioblastoma, brainstem glioma, poor prognosis malignant brain tumor, malignant glioma,recurrent malignant glioma, anaplastic astrocytoma, anaplasticoligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C& D colorectal cancer, unresectable colorectal carcinoma, metastatichepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblasticleukemia, chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma,non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Celllymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma,metastatic melanoma (localized melanoma, including, but not limited to,ocular melanoma), malignant mesothelioma, malignant pleural effusionmesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma,gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneousvasculitis, Langerhans cell histiocytosis, leiomyosarcoma,fibrodysplasia ossificans progressive, hormone refractory prostatecancer, resected high-risk soft tissue sarcoma, unrescectablehepatocellular carcinoma, Waldenstrom's macroglobulinemia, smolderingmyeloma, indolent myeloma, fallopian tube cancer, androgen independentprostate cancer, androgen dependent stage 1V non-metastatic prostatecancer, hormone-insensitive prostate cancer, chemotherapy-insensitiveprostate cancer, papillary thyroid carcinoma, follicular thyroidcarcinoma, medullary thyroid carcinoma, and leiomyoma. In a specificembodiment, the cancer is metastatic. In another embodiment, the canceris refractory or resistance to chemotherapy or radiation.

In one embodiment, provided herein are methods of treating, preventingor managing various forms of leukemias such as chronic lymphocyticleukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia,acute myelogenous leukemia and acute myeloblastic leukemia, includingleukemias that are relapsed, refractory or resistant, as disclosed inU.S. publication no. 2006/0030594, published Feb. 9, 2006, which isincorporated in its entirety by reference.

The term “leukemia” refers malignant neoplasms of the blood-formingtissues. The leukemia includes, but is not limited to, chroniclymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblasticleukemia, acute myelogenous leukemia and acute myeloblastic leukemia.The leukemia can be relapsed, refractory or resistant to conventionaltherapy. The term “relapsed” refers to a situation where patients whohave had a remission of leukemia after therapy have a return of leukemiacells in the marrow and a decrease in normal blood cells. The term“refractory or resistant” refers to a circumstance where patients, evenafter intensive treatment, have residual leukemia cells in their marrow.

In another embodiment, provided herein are methods of treating,preventing or managing various types of lymphomas, includingNon-Hodgkin's lymphoma (NHL). The term “lymphoma” refers a heterogenousgroup of neoplasms arising in the reticuloendothelial and lymphaticsystems. “NHL” refers to malignant monoclonal proliferation of lymphoidcells in sites of the immune system, including lymph nodes, bone marrow,spleen, liver and gastrointestinal tract. Examples of NHL include, butare not limited to, mantle cell lymphoma (MCL), lymphocytic lymphoma ofintermediate differentiation, intermediate lymphocytic lymphoma (ILL),diffuse poorly differentiated lymphocytic lymphoma (PDL), centrocyticlymphoma, diffuse small-cleaved cell lymphoma (DSCCL), follicularlymphoma, and any type of the mantle cell lymphomas that can be seenunder the microscope (nodular, diffuse, blastic and mentle zonelymphoma).

Examples of diseases and disorders associated with, or characterized by,undesired angiogenesis include, but are not limited to, inflammatorydiseases, autoimmune diseases, viral diseases, genetic diseases,allergic diseases, bacterial diseases, ocular neovascular diseases,choroidal neovascular diseases, retina neovascular diseases, andrubeosis (neovascularization of the angle). Specific examples of thediseases and disorders associated with, or characterized by, undesiredangiogenesis include, but are not limited to, arthritis, endometriosis,Crohn's disease, heart failure, advanced heart failure, renalimpairment, endotoxemia, toxic shock syndrome, osteoarthritis,retrovirus replication, wasting, meningitis, silica-induced fibrosis,asbestos-induced fibrosis, veterinary disorder, malignancy-associatedhypercalcemia, stroke, circulatory shock, periodontitis, gingivitis,macrocytic anemia, refractory anemia, and 5q-deletion syndrome.

Examples of pain include, but are not limited to those described in U.S.patent publication no. 2005/0203142, published Sep. 15, 2005, which isincorporated herein by reference. Specific types of pain include, butare not limited to, nociceptive pain, neuropathic pain, mixed pain ofnociceptive and neuropathic pain, visceral pain, migraine, headache andpost-operative pain.

Examples of nociceptive pain include, but are not limited to, painassociated with chemical or thermal burns, cuts of the skin, contusionsof the skin, osteoarthritis, rheumatoid arthritis, tendonitis, andmyofascial pain.

Examples of neuropathic pain include, but are not limited to, CRPS typeI, CRPS type II, reflex sympathetic dystrophy (RSD), reflexneurovascular dystrophy, reflex dystrophy, sympathetically maintainedpain syndrome, causalgia, Sudeck atrophy of bone, algoneurodystrophy,shoulder hand syndrome, post-traumatic dystrophy, trigeminal neuralgia,post herpetic neuralgia, cancer related pain, phantom limb pain,fibromyalgia, chronic fatigue syndrome, spinal cord injury pain, centralpost-stroke pain, radiculopathy, diabetic neuropathy, post-stroke pain,luetic neuropathy, and other painful neuropathic conditions such asthose induced by drugs such as vincristine and velcade.

As used herein, the terms “complex regional pain syndrome,” “CRPS” and“CRPS and related syndromes” mean a chronic pain disorder characterizedby one or more of the following: pain, whether spontaneous or evoked,including allodynia (painful response to a stimulus that is not usuallypainful) and hyperalgesia (exaggerated response to a stimulus that isusually only mildly painful); pain that is disproportionate to theinciting event (e.g., years of severe pain after an ankle sprain);regional pain that is not limited to a single peripheral nervedistribution; and autonomic dysregulation (e.g., edema, alteration inblood flow and hyperhidrosis) associated with trophic skin changes (hairand nail growth abnormalities and cutaneous ulceration).

Examples of MD and related syndromes include, but are not limited to,those described in U.S. patent publication no. 2004/0091455, publishedMay 13, 2004, which is incorporated herein by reference. Specificexamples include, but are not limited to, atrophic (dry) MD, exudative(wet) MD, age-related maculopathy (ARM), choroidal neovascularisation(CNVM), retinal pigment epithelium detachment (PED), and atrophy ofretinal pigment epithelium (RPE).

Examples of skin diseases include, but are not limited to, thosedescribed in U.S. publication no. 2005/0214328A1, published Sep. 29,2005, which is incorporated herein by reference. Specific examplesinclude, but are not limited to, keratoses and related symptoms, skindiseases or disorders characterized with overgrowths of the epidermis,acne, and wrinkles.

As used herein, the term “keratosis” refers to any lesion on theepidermis marked by the presence of circumscribed overgrowths of thehorny layer, including but not limited to actinic keratosis, seborrheickeratosis, keratoacanthoma, keratosis follicularis (Darier disease),inverted follicular keratosis, palmoplantar keratoderma (PPK, keratosispalmaris et plantaris), keratosis pilaris, and stucco keratosis. Theterm “actinic keratosis” also refers to senile keratosis, keratosissenilis, verruca senilis, plana senilis, solar keratosis, keratoderma orkeratoma. The term “seborrheic keratosis” also refers to seborrheicwart, senile wart, or basal cell papilloma. Keratosis is characterizedby one or more of the following symptoms: rough appearing, scaly,erythematous papules, plaques, spicules or nodules on exposed surfaces(e.g., face, hands, ears, neck, legs and thorax), excrescences ofkeratin referred to as cutaneous horns, hyperkeratosis, telangiectasias,elastosis, pigmented lentigines, acanthosis, parakeratosis,dyskeratoses, papillomatosis, hyperpigmentation of the basal cells,cellular atypia, mitotic figures, abnormal cell-cell adhesion, denseinflammatory infiltrates and small prevalence of squamous cellcarcinomas.

Examples of skin diseases or disorders characterized with overgrowths ofthe epidermis include, but are not limited to, any conditions, diseasesor disorders marked by the presence of overgrowths of the epidermis,including but not limited to, infections associated with papillomavirus, arsenical keratoses, sign of Leser-Trelat, warty dyskeratoma(WD), trichostasis spinulosa (TS), erythrokeratodermia variabilis (EKV),ichthyosis fetalis (harlequin ichthyosis), knuckle pads, cutaneousmelanoacanthoma, porokeratosis, psoriasis, squamous cell carcinoma,confluent and reticulated papillomatosis (CRP), acrochordons, cutaneoushorn, cowden disease (multiple hamartoma syndrome), dermatosis papulosanigra (DPN), epidermal nevus syndrome (ENS), ichthyosis vulgaris,molluscum contagiosum, prurigo nodularis, and acanthosis nigricans (AN).

Examples of pulmonary disorders include, but are not limited to, thosedescribed in U.S. publication no. 2005/0239842A1, published Oct. 27,2005, which is incorporated herein by reference. Specific examplesinclude pulmonary hypertension and related disorders. Examples ofpulmonary hypertension and related disorders include, but are notlimited to: primary pulmonary hypertension (PPH); secondary pulmonaryhypertension (SPH); familial PPH; sporadic PPH; precapillary pulmonaryhypertension; pulmonary arterial hypertension (PAH); pulmonary arteryhypertension; idiopathic pulmonary hypertension; thrombotic pulmonaryarteriopathy (TPA); plexogenic pulmonary arteriopathy; functionalclasses I to IV pulmonary hypertension; and pulmonary hypertensionassociated with, related to, or secondary to, left ventriculardysfunction, mitral valvular disease, constrictive pericarditis, aorticstenosis, cardiomyopathy, mediastinal fibrosis, anomalous pulmonaryvenous drainage, pulmonary venoocclusive disease, collagen vasulardisease, congenital heart disease, HIV virus infection, drugs and toxinssuch as fenfluramines, congenital heart disease, pulmonary venoushypertension, chronic obstructive pulmonary disease, interstitial lungdisease, sleep-disordered breathing, alveolar hypoventilation disorder,chronic exposure to high altitude, neonatal lung disease,alveolar-capillary dysplasia, sickle cell disease, other coagulationdisorder, chronic thromboemboli, connective tissue disease, lupusincluding systemic and cutaneous lupus, schistosomiasis, sarcoidosis orpulmonary capillary hemangiomatosis.

Examples of asbestos-related disorders include, but not limited to,those described in U.S. publication no. 2005/0100529, published May 12,2005, which is incorporated herein by reference. Specific examplesinclude, but are not limited to, mesothelioma, asbestosis, malignantpleural effusion, benign exudative effusion, pleural plaques, pleuralcalcification, diffuse pleural thickening, rounded atelectasis, fibroticmasses, and lung cancer.

Examples of parasitic diseases include, but are not limited to, thosedescribed in U.S. publication no. 2006/0154880, published Jul. 13, 2006,which is incorporated herein by reference. Parasitic diseases includediseases and disorders caused by human intracellular parasites such as,but not limited to, P. fallciarium, P. ovale, P. vivax, P. malariae, L.donovari, L. infantum, L. aethiopica, L. major, L. tropica, L. mexicana,L. braziliensis, T Gondii, B. microti, B. divergens, B. coli, C. parvum,C. cayetanensis, E. histolytica, I. belli, S. mansonii, S. haematobium,Trypanosoma ssp., Toxoplasma ssp., and O. volvulus. Other diseases anddisorders caused by non-human intracellular parasites such as, but notlimited to, Babesia bovis, Babesia canis, Banesia Gibsoni, Besnoitliadarlingi, Cytauxzoon felis, Eimeria ssp., Hammondia ssp., and Theileriassp., are also encompassed. Specific examples include, but are notlimited to, malaria, babesiosis, trypanosomiasis, leishmaniasis,toxoplasmosis, meningoencephalitis, keratitis, amebiasis, giardiasis,cryptosporidiosis, isosporiasis, cyclosporiasis, microsporidiosis,ascariasis, trichuriasis, ancylostomiasis, strongyloidiasis,toxocariasis, trichinosis, lymphatic filariasis, onchocerciasis,filariasis, schistosomiasis, and dermatitis caused by animalschistosomes.

Examples of immunodeficiency disorders include, but are not limited to,those described in U.S. publication no. 2006/0188475, published Aug. 24,2006. Specific examples include, but not limited to, adenosine deaminasedeficiency, antibody deficiency with normal or elevated Igs,ataxia-tenlangiectasia, bare lymphocyte syndrome, common variableimmunodeficiency, Ig deficiency with hyper-IgM, Ig heavy chaindeletions, IgA deficiency, immunodeficiency with thymoma, reticulardysgenesis, Nezelof syndrome, selective IgG subclass deficiency,transient hypogammaglobulinemia of infancy, Wistcott-Aldrich syndrome,X-linked agammaglobulinemia, X-linked severe combined immunodeficiency.

Examples of CNS disorders include, but are not limited to, thosedescribed in U.S. publication no. 2005/0143344, published Jun. 30, 2005,which is incorporated herein by reference. Specific examples include,but are not limited to, include, but are not limited to, AmyotrophicLateral Sclerosis, Alzheimer Disease, Parkinson Disease, Huntington'sDisease, Multiple Sclerosis other neuroimmunological disorders such asTourette Syndrome, delerium, or disturbances in consciousness that occurover a short period of time, and amnestic disorder, or discreet memoryimpairments that occur in the absence of other central nervous systemimpairments.

Examples of CNS injuries and related syndromes include, but are notlimited to, those described in U.S. publication no. 2006/0122228,published Jun. 8, 2006, which is incorporated herein by reference.Specific examples include, but are not limited to, CNS injury/damage andrelated syndromes, include, but are not limited to, primary braininjury, secondary brain injury, traumatic brain injury, focal braininjury, diffuse axonal injury, head injury, concussion, post-concussionsyndrome, cerebral contusion and laceration, subdural hematoma,epidermal hematoma, post-traumatic epilepsy, chronic vegetative state,complete SCI, incomplete SCI, acute SCI, subacute SCl, chronic SCI,central cord syndrome, Brown-Sequard syndrome, anterior cord syndrome,conus medullaris syndrome, cauda equina syndrome, neurogenic shock,spinal shock, altered level of consciousness, headache, nausea, emesis,memory loss, dizziness, diplopia, blurred vision, emotional lability,sleep disturbances, irritability, inability to concentrate, nervousness,behavioral impairment, cognitive deficit, and seizure.

Other disease or disorders include, but not limited to, viral, genetic,allergic, and autoimmune diseases. Specific examples include, but notlimited to, HIV, hepatitis, adult respiratory distress syndrome, boneresorption diseases, chronic pulmonary inflammatory diseases,dermatitis, cystic fibrosis, septic shock, sepsis, endotoxic shock,hemodynamic shock, sepsis syndrome, post ischemic reperfusion injury,meningitis, psoriasis, fibrotic disease, cachexia, graft versus hostdisease, graft rejection, auto-immune disease, rheumatoid spondylitis,Crohn's disease, ulcerative colitis, inflammatory-bowel disease,multiple sclerosis, systemic lupus erythrematosus, ENL in leprosy,radiation damage, cancer, asthma, or hyperoxic alveolar injury.

Examples of atherosclerosis and related conditions include, but are notlimited to, those disclosed in U.S. publication no. 2002/0054899,published May 9, 2002, which is incorporated herein by reference.Specific examples include, but are not limited to, all forms ofconditions involving atherosclerosis, including restenosis aftervascular intervention such as angioplasty, stenting, atherectomy andgrafting. All forms of vascular intervention are contemplated herein,including diseases of the cardiovascular and renal system, such as, butnot limited to, renal angioplasty, percutaneous coronary intervention(PCI), percutaneous transluminal coronary angioplasty (PTCA), carotidpercutaneous transluminal angioplasty (PTA), coronary by-pass grafting,angioplasty with stent implantation, peripheral percutaneoustransluminal intervention of the iliac, femoral or popliteal arteries,and surgical intervention using impregnated artificial grafts. Thefollowing chart provides a listing of the major systemic arteries thatmay be in need of treatment, all of which are contemplated herein:

Artery Body Areas Supplied Axillary Shoulder and axilla Brachial Upperarm Brachiocephalic Head, neck, and arm Celiac Divides into leftgastric, splenic, and hepatic arteries Common carotid Neck Common iliacDivides into external and internal iliac arteries Coronary Heart Deepfemoral Thigh Digital Fingers Dorsalis pedis Foot External carotid Neckand external head regions External iliac Femoral artery Femoral ThighGastric Stomach Hepatic Liver, gallbladder, pancreas, and duodenumInferior mesenteric Descending colon, rectum, and pelvic wall Internalcarotid Neck and internal head regions Internal iliac Rectum, urinarybladder, external genitalia, buttocks muscles, uterus and vagina Leftgastric Esophagus and stomach Middle sacral Sacrum Ovarian OvariesPalmar arch Hand Peroneal Calf Popliteal Knee Posterior tibial CalfPulmonary Lungs Radial Forearm Renal Kidney Splenic Stomach, pancreas,and spleen Subclavian Shoulder Superior mesenteric Pancreas, smallintestine, ascending and transverse colon Testicular Testes UlnarForearm

Examples of dysfunctional sleep and related syndromes include, but arenot limited to, those disclosed in U.S. publication no. 2005/0222209A1,published Oct. 6, 2005, which is incorporated herein by reference.Specific examples include, but are not limited to, snoring, sleep apnea,insomnia, narcolepsy, restless leg syndrome, sleep terrors, sleepwalking sleep eating, and dysfunctional sleep associated with chronicneurological or inflammatory conditions. Chronic neurological orinflammatory conditions, include, but are not limited to, ComplexRegional Pain Syndrome, chronic low back pain, musculoskeletal pain,arthritis, radiculopathy, pain associated with cancer, fibromyalgia,chronic fatigue syndrome, visceral pain, bladder pain, chronicpancreatitis, neuropathies (diabetic, post-herpetic, traumatic orinflammatory), and neurodegenerative disorders such as Parkinson'sDisease, Alzheimer's Disease, amyotrophic lateral sclerosis, multiplesclerosis, Huntington's Disease, bradykinesia; muscle rigidity;parkinsonian tremor; parkinsonian gait; motion freezing; depression;defective long-term memory, Rubinstein-Taybi syndrome (RTS); dementia;postural instability; hypokinetic disorders; synuclein disorders;multiple system atrophies; striatonigral degeneration;olivopontocerebellar atrophy; Shy-Drager syndrome; motor neuron diseasewith parkinsonian features; Lewy body dementia; Tau pathology disorders;progressive supranuclear palsy; corticobasal degeneration;frontotemporal dementia; amyloid pathology disorders; mild cognitiveimpairment; Alzheimer disease with parkinsonism; Wilson disease;Hallervorden-Spatz disease; Chediak-Hagashi disease; SCA-3spinocerebellar ataxia; X-linked dystonia parkinsonism; prion disease;hyperkinetic disorders; chorea; ballismus; dystonia tremors; AmyotrophicLateral Sclerosis (ALS); CNS trauma and myoclonus.

Examples of hemoglobinopathy and related disorders include, but are notlimited to, those described in U.S. publication no. 2005/0143420A1,published Jun. 30, 2005, which is incorporated herein by reference.Specific examples include, but are not limited to, hemoglobinopathy,sickle cell anemia, and any other disorders related to thedifferentiation of CD34+ cells.

Examples of TNFα related disorders include, but are not limited to,those described in WO 98/03502 and WO 98/54170, both of which areincorporated herein in their entireties by reference. Specific examplesinclude, but are not limited to: endotoxemia or toxic shock syndrome;cachexia; adult respiratory distress syndrome; bone resorption diseasessuch as arthritis; hypercalcemia; Graft versus Host Reaction; cerebralmalaria; inflammation; tumor growth; chronic pulmonary inflammatorydiseases; reperfusion injury; myocardial infarction; stroke; circulatoryshock; rheumatoid arthritis; Crohn's disease; HIV infection and AIDS;other disorders such as rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, psoriatic arthritis and other arthritic conditions,septic shock, septis, endotoxic shock, graft versus host disease,wasting, Crohn's disease, ulcerative colitis, multiple sclerosis,systemic lupus erythromatosis, ENL in leprosy, HIV, AIDS, andopportunistic infections in AIDS; disorders such as septic shock,sepsis, endotoxic shock, hemodynamic shock and sepsis syndrome, postischemic reperfusion injury, malaria, mycobacterial infection,meningitis, psoriasis, congestive heart failure, fibrotic disease,cachexia, graft rejection, oncogenic or cancerous conditions, asthma,autoimmune disease, radiation damages, and hyperoxic alveolar injury;viral infections, such as those caused by the herpes viruses; viralconjunctivitis; or atopic dermatitis.

Other embodiments provide the use of compounds provided herein invarious immunological applications, in particular, as vaccine adjuvants,in particular, as anticancer vaccine adjuvants. In certain embodimentsthe compounds provided herein may be used as anticancer vaccineadjuvants according to the methods disclosed in U.S. publication no.2007/0048327, published Mar. 1, 2007, which is incorporated herein inits entirety by reference. These embodiments also relate to the uses ofcompounds provided herein in combination with vaccines to treat orprevent cancer or infectious diseases, and other various uses ofimmunomodulatory compounds such as reduction or desensitization ofallergic reactions.

Doses of a compound provided herein, or a pharmaceutically acceptablesalt, solvate, clathrate, stereoisomer or prodrug thereof, varydepending on factors such as: specific indication to be treated,prevented, or managed; age and condition of a patient; and amount ofsecond active agent used, if any. Generally, a compound provided herein,or a pharmaceutically acceptable salt, solvate, clathrate, stereoisomeror prodrug thereof, may be used in an amount of from about 0.1 mg toabout 500 mg per day, and can be adjusted in a conventional fashion(e.g., the same amount administered each day of the treatment,prevention or management period), in cycles (e.g., one week on, one weekoff), or in an amount that increases or decreases over the course oftreatment, prevention, or management. In other embodiments, the dose canbe from about 1 mg to about 300 mg, from about 0.1 mg to about 150 mg,from about 1 mg to about 200 mg, from about 10 mg to about 100 mg, fromabout 0.1 mg to about 50 mg, from about 1 mg to about 50 mg, from about10 mg to about 50 mg, from about 20 mg to about 30 mg, or from about 1mg to about 20 mg.

5.4 Second Active Agents

In certain embodiments, a solid form provided herein is administered incombination with another drug (“second active agent”) or treatment.Second active agents can be large molecules (e.g., proteins) or smallmolecules (e.g., synthetic inorganic, organometallic, or organicmolecules), examples of which are provided herein, as well as stemcells. Methods, or therapies, that can be used in combination with theadministration of compounds provided herein include, but are not limitedto, surgery, blood transfusions, immunotherapy, biological therapy,radiation therapy, and other non-drug based therapies presently used totreat, prevent or manage various disorders described herein. Certaincombinations may work synergistically in the treatment of particulartypes diseases or disorders, and conditions and symptoms associated withsuch diseases or disorders. A solid form provided herein can also workto alleviate adverse effects associated with certain second activeagents, and vice versa.

Examples of large molecule active agents include, but are not limitedto, hematopoietic growth factors, cytokines, and monoclonal andpolyclonal antibodies. Specific examples of the active agents areanti-CD40 monoclonal antibodies (such as, for example, SGN-40); histonedeacetylyase inhibitors (such as, for example, SAHA and LAQ 824);heat-shock protein-90 inhibitors (such as, for example, 17-AAG);insulin-like growth factor-1 receptor kinase inhibitors; vascularendothelial growth factor receptor kinase inhibitors (such as, forexample, PTK787); insulin growth factor receptor inhibitors;lysophosphatidic acid acyltransrerase inhibitors; IkB kinase inhibitors;p38MAPK inhibitors; EGFR inhibitors (such as, for example, gefitinib anderlotinib HCL); HER-2 antibodies (such as, for example, trastuzumab(Herceptin®) and pertuzumab (Omnitarg™)); VEGFR antibodies (such as, forexample, bevacizumab (Avastin™)); VEGFR inhibitors (such as, forexample, flk-1 specific kinase inhibitors, SU5416 and ptk787/zk222584);P13K inhibitors (such as, for example, wortmannin); C-Met inhibitors(such as, for example, PHA-665752); monoclonal antibodies (such as, forexample, rituximab (Rituxan®), tositumomab (Bexxar®), edrecolomab(Panorex®) and G250); and anti-TNF-α antibodies. Examples of smallmolecule active agents include, but are not limited to, anticanceragents (e.g., lapatinib (Tykerbik®)) and antibiotics (e.g.,clarithromycin).

Specific second active compounds that can be combined with compoundsprovided herein vary depending on the specific indication to be treated,prevented or managed.

For instance, for the treatment, prevention or management of cancer,second active agents include, but are not limited to: semaxanib;cyclosporin; etanercept; doxycycline; bortezomib; acivicin; aclarubicin;acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine;ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin;asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat;benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol; celecoxib;chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;esorubicin hydrochloride; estramustine; estramustine phosphate sodium;etanidazole; etoposide; etoposide phosphate; etoprine; fadrozolehydrochloride; fazarabine; fenretinide; floxuridine; fludarabinephosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; safingol; safingol hydrochloride; semustine;simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur;teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicinhydrochloride.

Other second agents include, but are not limited to: 20-epi-1,25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel;docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene;dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine;edrecolomab; eflomithine; elemene; emitefur; epirubicin; epristeride;estramustine analogue; estrogen agonists; estrogen antagonists;etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine;fenretinide; filgrastim; finasteride; flavopiridol; flezelastine;fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex;formestane; fostriecin; fotemustine; gadolinium texaphyrin; galliumnitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;glutathione inhibitors; hepsulfam; heregulin; hexamethylenebisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;idramantone; ilmofosine; ilomastat; imatinib (Gleevec®), imiquimod;immunostimulant peptides; insulin-like growth factor-1 receptorinhibitor; interferon agonists; interferons; interleukins; iobenguane;iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole;isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F;lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinansulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocytealpha interferon; leuprolide+estrogen+progesterone; leuprorelin;levamisole; liarozole; linear polyamine analogue; lipophilicdisaccharide peptide; lipophilic platinum compounds; lissoclinamide 7;lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lyticpeptides; maitansine; mannostatin A; marimastat; masoprocol; maspin;matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril;merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor;mifepristone; miltefosine; mirimostim; mitoguazone; mitolactol;mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; Erbitux, humanchorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wallsk; mopidamol; mustard anticancer agent; mycaperoxide B; mycobacterialcell wall extract; myriaporone; N-acetyldinaline; N-substitutedbenzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin;naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant;nitrullyn; oblimersen (Genasense®); O6-benzylguanine; octreotide;okicenone; oligonucleotides; onapristone; ondansetron; ondansetron;oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin;oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives;palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene;parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfatesodium; pentostatin; pentrozole; perflubron; perfosfamide; perillylalcohol; phenazinomycin; phenylacetate; phosphatase inhibitors;picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetinA; placetin B; plasminogen activator inhibitor; platinum complex;platinum compounds; platinum-triamine complex; porfimer sodium;porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;proteasome inhibitors; protein A-based immune modulator; protein kinaseC inhibitor; protein kinase C inhibitors, microalgal; protein tyrosinephosphatase inhibitors; purine nucleoside phosphorylase inhibitors;purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethyleneconjugate; raf antagonists; raltitrexed; ramosetron; ras farnesylprotein transferase inhibitors; ras inhibitors; ras-GAP inhibitor;retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;ribozymes; RII retinamide; rohitukine; romurtide; roquinimex; rubiginoneB1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim;Sdi 1 mimetics; semustine; senescence derived inhibitor 1; senseoligonucleotides; signal transduction inhibitors; sizofiran; sobuzoxane;sodium borocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stipiamide; stromelysininhibitors; sulfinosine; superactive vasoactive intestinal peptideantagonist; suradista; suramin; swainsonine; tallimustine; tamoxifenmethiodide; tauromustine; tazarotene; tecogalan sodium; tegafur;tellurapyrylium; telomerase inhibitors; temoporfin; teniposide;tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietinreceptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyletiopurpurin; tirapazamine; titanocene bichloride; topsentin;toremifene; translation inhibitors; tretinoin; triacetyluridine;triciribine; trimetrexate; triptorelin; tropisetron; turosteride;tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;urogenital sinus-derived growth inhibitory factor; urokinase receptorantagonists; vapreotide; variolin B; velaresol; veramine; verdins;verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone;zeniplatin; zilascorb; and zinostatin stimalamer.

Specific second active agents include, but are not limited to,2-methoxyestradiol, telomestatin, inducers of apoptosis in mutiplemyeloma cells (such as, for example, TRAIL), statins, semaxanib,cyclosporin, etanercept, doxycycline, bortezomib, oblimersen(Genasense®), remicade, docetaxel, celecoxib, melphalan, dexamethasone(Decadron®), steroids, gemcitabine, cisplatinum, temozolomide,etoposide, cyclophosphamide, temodar, carboplatin, procarbazine,gliadel, tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxotere,fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha,pegylated interferon alpha (e.g., PEG INTRON-A), capecitabine,cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin,cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF,dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin,busulphan, prednisone, bisphosphonate, arsenic trioxide, vincristine,doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustinesodium phosphate (Emcyt®), sulindac, and etoposide.

In another embodiment, examples of specific second agents according tothe indications to be treated, prevented, or managed can be found in thefollowing references, all of which are incorporated herein in theirentireties: U.S. Pat. Nos. 6,281,230 and 5,635,517; U.S. publicationnos. 2004/0220144, 2004/0190609, 2004/0087546, 2005/0203142,2004/0091455, 2005/0100529, 2005/0214328, 2005/0239842, 2006/0154880,2006/0122228, and 2005/0143344; and U.S. provisional application No.60/631,870.

Examples of second active agents that may be used for the treatment,prevention and/or management of pain include, but are not limited to,conventional therapeutics used to treat or prevent pain such asantidepressants, anticonvulsants, antihypertensives, anxiolytics,calcium channel blockers, muscle relaxants, non-narcotic analgesics,opioid analgesics, anti-inflammatories, cox-2 inhibitors,immunomodulatory agents, alpha-adrenergic receptor agonists orantagonists, immunosuppressive agents, corticosteroids, hyperbaricoxygen, ketamine, other anesthetic agents, NMDA antagonists, and othertherapeutics found, for example, in the Physician's Desk Reference 2003.Specific examples include, but are not limited to, salicylic acidacetate (Aspirin®), celecoxib (Celebrex®), Enbrel®, ketamine, gabapentin(Neurontin®), phenyloin (Dilantin®), carbamazepine (Tegretol®),oxcarbazepine (Trileptal®), valproic acid (Depakene®), morphine sulfate,hydromorphone, prednisone, griseofulvin, penthonium, alendronate,dyphenhydramide, guanethidine, ketorolac (Acular®), thyrocalcitonin,dimethylsulfoxide (DMSO), clonidine (Catapress®), bretylium, ketanserin,reserpine, droperidol, atropine, phentolamine, bupivacaine, lidocaine,acetaminophen, nortriptyline (Pamelor®), amitriptyline (Elavil®),imipramine (Tofranil®), doxepin (Sinequan®), clomipramine (Anafranil®),fluoxetine (Prozac®), sertraline (Zoloft®), naproxen, nefazodone(Serzone®), venlafaxine (Effexor®), trazodone (Desyrel®), bupropion(Wellbutrin®), mexiletine, nifedipine, propranolol, tramadol,lamotrigine, vioxx, ziconotide, ketamine, dextromethorphan,benzodiazepines, baclofen, tizanidine and phenoxybenzamine.

Examples of second active agents that may be used for the treatment,prevention and/or management of macular degeneration and relatedsyndromes include, but are not limited to, a steroid, a lightsensitizer, an integrin, an antioxidant, an interferon, a xanthinederivative, a growth hormone, a neutrotrophic factor, a regulator ofneovascularization, an anti-VEGF antibody, a prostaglandin, anantibiotic, a phytoestrogen, an anti-inflammatory compound or anantiangiogenesis compound, or a combination thereof. Specific examplesinclude, but are not limited to, verteporfin, purlytin, an angiostaticsteroid, rhuFab, interferon-2α, pentoxifylline, tin etiopurpurin,motexafin, lucentis, lutetium,9-fluoro-11,21-dihydroxy-16,17-1-methylethylidinebis(oxy)pregna-1,4-diene-3,20-dione,latanoprost (see U.S. Pat. No. 6,225,348), tetracycline and itsderivatives, rifamycin and its derivatives, macrolides, metronidazole(U.S. Pat. Nos. 6,218,369 and 6,015,803), genistein, genistin, 6′-O-Malgenistin, 6′-O—Ac genistin, daidzein, daidzin, 6′-O-Mal daidzin, 6′-O—Acdaidzin, glycitein, glycitin, 6′-O-Mal glycitin, biochanin A,formononetin (U.S. Pat. No. 6,001,368), triamcinolone acetomide,dexamethasone (U.S. Pat. No. 5,770,589), thalidomide, glutathione (U.S.Pat. No. 5,632,984), basic fibroblast growth factor (bFGF), transforminggrowth factor b (TGF-b), brain-derived neurotrophic factor (BDNF),plasminogen activator factor type 2 (PAI-2), EYE101 (EyetechPharmaceuticals), LY333531 (Eli Lilly), Miravant, and RETISERT implant(Bausch & Lomb). All of the references cited herein are incorporated intheir entireties by reference.

Examples of second active agents that may be used for the treatment,prevention and/or management of skin diseases include, but are notlimited to, keratolytics, retinoids, α-hydroxy acids, antibiotics,collagen, botulinum toxin, interferon, steroids, and immunomodulatoryagents. Specific examples include, but are not limited to,5-fluorouracil, masoprocol, trichloroacetic acid, salicylic acid, lacticacid, ammonium lactate, urea, tretinoin, isotretinoin, antibiotics,collagen, botulinum toxin, interferon, corticosteroid, transretinoicacid and collagens such as human placental collagen, animal placentalcollagen, Dermalogen, AlloDerm, Fascia, Cymetra, Autologen, Zyderm,Zyplast, Resoplast, and Isolagen.

Examples of second active agents that may be used for the treatment,prevention and/or management of pulmonary hepertension and relateddisorders include, but are not limited to, anticoagulants, diuretics,cardiac glycosides, calcium channel blockers, vasodilators, prostacyclinanalogues, endothelin antagonists, phosphodiesterase inhibitors (e.g.,PDE V inhibitors), endopeptidase inhibitors, lipid lowering agents,thromboxane inhibitors, and other therapeutics known to reduce pulmonaryartery pressure. Specific examples include, but are not limited to,warfarin (Coumadin®)), a diuretic, a cardiac glycoside, digoxin-oxygen,diltiazem, nifedipine, a vasodilator such as prostacyclin (e.g.,prostaglandin 12 (PGI2), epoprostenol (EPO, Floran®), treprostinil(Remodulin®), nitric oxide (NO), bosentan (Tracleer®), amlodipine,epoprostenol (Floran®), treprostinil (Remodulin®), prostacyclin,tadalafil (Clalis®), simvastatin (Zocor®), omapatrilat (Vanlev®),irbesartan (Avapro®), pravastatin (Pravacholt®)), digoxin, L-arginine,iloprost, betaprost, and sildenafil (Viagra®).

Examples of second active agents that may be used for the treatment,prevention and/or management of asbestos-related disorders include, butare not limited to, anthracycline, platinum, alkylating agent,oblimersen (Genasense®), cisplatinum, cyclophosphamide, temodar,carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate,taxotere, irinotecan, capecitabine, cisplatin, thiotepa, fludarabine,carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel,vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid,palmitronate, biaxin, busulphan, prednisone, bisphosphonate, arsenictrioxide, vincristine, doxorubicin (Doxil®), paclitaxel, ganciclovir,adriamycin, bleomycin, hyaluronidase, mitomycin C, mepacrine, thiotepa,tetracycline and gemcitabine.

Examples of second active agents that may be used for the treatment,prevention and/or management of parasitic diseases include, but are notlimited to, chloroquine, quinine, quinidine, pyrimethamine,sulfadiazine, doxycycline, clindamycin, mefloquine, halofantrine,primaquine, hydroxychloroquine, proguanil, atovaquone, azithromycin,suramin, pentamidine, melarsoprol, nifurtimox, benznidazole,amphotericin B, pentavalent antimony compounds (e.g., sodiumstiboglucuronate), interfereon gamma, itraconazole, a combination ofdead promastigotes and BCG, leucovorin, corticosteroids, sulfonamide,spiramycin, IgG (serology), trimethoprim, and sulfamethoxazole.

Examples of second active agents that may be used for the treatment,prevention and/or management of immunodeficiency disorders include, butare not limited to: antibiotics (therapeutic or prophylactic) such as,but not limited to, ampicillin, tetracycline, penicillin,cephalosporins, streptomycin, kanamycin, and erythromycin; antiviralssuch as, but not limited to, amantadine, rimantadine, acyclovir, andribavirin; immunoglobulin; plasma; immunologic enhancing drugs such as,but not limited to, levami sole and isoprinosine; biologics such as, butnot limited to, gammaglobulin, transfer factor, interleukins, andinterferons; hormones such as, but not limited to, thymic; and otherimmunologic agents such as, but not limited to, B cell stimulators(e.g., BAFF/BlyS), cytokines (e.g., IL-2, IL-4, and IL-5), growthfactors (e.g., TGF-α), antibodies (e.g., anti-CD40 and IgM),oligonucleotides containing unmethylated CpG motifs, and vaccines (e.g.,viral and tumor peptide vaccines).

Examples of second active agents that may be used for the treatment,prevention and/or management of CNS disorders include, but are notlimited to: opioids; a dopamine agonist or antagonist, such as, but notlimited to, Levodopa, L-DOPA, cocaine, α-methyl-tyrosine, reserpine,tetrabenazine, benzotropine, pargyline, fenodolpam mesylate,cabergoline, pramipexole dihydrochloride, ropinorole, amantadinehydrochloride, selegiline hydrochloride, carbidopa, pergolide mesylate,Sinemet CR, and Symmetrel; a MAO inhibitor, such as, but not limited to,iproniazid, clorgyline, phenelzine and isocarboxazid; a COMT inhibitor,such as, but not limited to, tolcapone and entacapone; a cholinesteraseinhibitor, such as, but not limited to, physostigmine saliclate,physostigmine sulfate, physostigmine bromide, meostigmine bromide,neostigmine methylsulfate, ambenonim chloride, edrophonium chloride,tacrine, pralidoxime chloride, obidoxime chloride, trimedoxime bromide,diacetyl monoxim, endrophonium, pyridostigmine, and demecarium; ananti-inflammatory agent, such as, but not limited to, naproxen sodium,diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin,diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone,refecoxib, methotrexate, leflunomide, sulfasalazine, gold salts, Rho-DImmune Globulin, mycophenylate mofetil, cyclosporine, azathioprine,tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylicacid, methyl salicylate, diflunisal, salsalate, olsalazine,sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid,meclofenamate sodium, tolmetin, ketorolac, dichlofenac, flurbinprofen,oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam,tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine,apazone, zileuton, aurothioglucose, gold sodium thiomalate, auranofin,methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone andbenzbromarone or betamethasone and other glucocorticoids; and anantiemetic agent, such as, but not limited to, metoclopromide,domperidone, prochlorperazine, promethazine, chlorpromazine,trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucinemonoethanolamine, alizapride, azasetron, benzquinamide, bietanautine,bromopride, buclizine, clebopride, cyclizine, dimenhydrinate,diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone,oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol,thiethylperazine, thioproperazine, tropisetron, and a mixture thereof.

Examples of second active agents that may be used for the treatment,prevention and/or management of CNS injuries and related syndromesinclude, but are not limited to, immunomodulatory agents,immunosuppressive agents, antihypertensives, anticonvulsants,fibrinolytic agents, antiplatelet agents, antipsychotics,antidepressants, benzodiazepines, buspirone, amantadine, and other knownor conventional agents used in patients with CNS injury/damage andrelated syndromes. Specific examples include, but are not limited to:steroids (e.g., glucocorticoids, such as, but not limited to,methylprednisolone, dexamethasone and betamethasone); ananti-inflammatory agent, including, but not limited to, naproxen sodium,diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin,diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone,refecoxib, methotrexate, leflunomide, sulfasalazine, gold salts, RHo-DImmune Globulin, mycophenylate mofetil, cyclosporine, azathioprine,tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylicacid, methyl salicylate, diflunisal, salsalate, olsalazine,sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid,meclofenamate sodium, tolmetin, ketorolac, dichlofenac, flurbinprofen,oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam,tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine,apazone, zileuton, aurothioglucose, gold sodium thiomalate, auranofin,methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone andbenzbromarone; a cAMP analog including, but not limited to, db-cAMP; anagent comprising a methylphenidate drug, which comprises1-threo-methylphenidate, d-threo-methylphenidate,dl-threo-methylphenidate, 1-erythro-methylphenidate,d-erythro-methylphenidate, dl-erythro-methylphenidate, and a mixturethereof; and a diuretic agent such as, but not limited to, mannitol,furosemide, glycerol, and urea.

Examples of second active agent that may be used for the treatment,prevention and/or management of dysfunctional sleep and relatedsyndromes include, but are not limited to, a tricyclic antidepressantagent, a selective serotonin reuptake inhibitor, an antiepileptic agent(gabapentin, pregabalin, carbamazepine, oxcarbazepine, levitiracetam,topiramate), an antiaryhthmic agent, a sodium channel blocking agent, aselective inflammatory mediator inhibitor, an opioid agent, a secondimmunomodulatory compound, a combination agent, and other known orconventional agents used in sleep therapy. Specific examples include,but are not limited to, Neurontin, oxycontin, morphine, topiramate,amitryptiline, nortryptiline, carbamazepine, Levodopa, L-DOPA, cocaine,α-methyl-tyrosine, reserpine, tetrabenazine, benzotropine, pargyline,fenodolpam mesylate, cabergoline, pramipexole dihydrochloride,ropinorole, amantadine hydrochloride, selegiline hydrochloride,carbidopa, pergolide mesylate, Sinemet CR, Symmetrel, iproniazid,clorgyline, phenelzine, isocarboxazid, tolcapone, entacapone,physostigmine saliclate, physostigmine sulfate, physostigmine bromide,meostigmine bromide, neostigmine methylsulfate, ambenonim chloride,edrophonium chloride, tacrine, pralidoxime chloride, obidoxime chloride,trimedoxime bromide, diacetyl monoxim, endrophonium, pyridostigmine,demecarium, naproxen sodium, diclofenac sodium, diclofenac potassium,celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam,ibuprofen, ketoprofen, nabumetone, refecoxib, methotrexate, leflunomide,sulfasalazine, gold salts, RHo-D Immune Globulin, mycophenylate mofetil,cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab,salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal,salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin,sulindac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac,dichlofenac, flurbinprofen, oxaprozin, piroxicam, meloxicam,ampiroxicam, droxicam, pivoxicam, tenoxicam, phenylbutazone,oxyphenbutazone, antipyrine, aminopyrine, apazone, zileuton,aurothioglucose, gold sodium thiomalate, auranofin, methotrexate,colchicine, allopurinol, probenecid, sulfinpyrazone, benzbromarone,betamethasone and other glucocorticoids, metoclopromide, domperidone,prochlorperazine, promethazine, chlorpromazine, trimethobenzamide,ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine,alizapride, azasetron, benzquinamide, bietanautine, bromopride,buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol,dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl,pipamazine, scopolamine, sulpiride, tetrahydrocannabinol,thiethylperazine, thioproperazine, tropisetron, and a mixture thereof.

Examples of second active agents that may be used for the treatment,prevention and/or management of hemoglobinopathy and related disordersinclude, but are not limited to: interleukins, such as IL-2 (includingrecombinant IL-II (“rIL2”) and canarypox IL-2), IL-10, IL-12, and IL-18;interferons, such as interferon alfa-2a, interferon alfa-2b, interferonalfa-n1, interferon alfa-n3, interferon beta-I a, and interferon gamma-Ib; and G-CSF; hydroxyurea; butyrates or butyrate derivatives; nitrousoxide; hydroxy urea; HEMOXIN™ (IPRISAN™; see U.S. Pat. No. 5,800,819);Gardos channel antagonists such as clotrimazole and triaryl methanederivatives; Deferoxamine; protein C; and transfusions of blood, or of ablood substitute such as Hemospan™ or Hemospan™ PS (Sangart).

Administration of a compound provided herein, or a pharmaceuticallyacceptable salt, solvate, clathrate, stereoisomer or prodrug thereof,and the second active agents to a patient can occur simultaneously orsequentially by the same or different routes of administration. Thesuitability of a particular route of administration employed for aparticular active agent will depend on the active agent itself (e.g.,whether it can be administered orally without decomposing prior toentering the blood stream) and the disease being treated. One ofadministration for compounds provided herein is oral. Routes ofadministration for the second active agents or ingredients are known tothose of ordinary skill in the art. See, e.g., Physicians' DeskReference (60^(th) ed., 2006).

In one embodiment, the second active agent is administered intravenouslyor subcutaneously and once or twice daily in an amount of from about 1to about 1000 mg, from about 5 to about 500 mg, from about 10 to about350 mg, or from about 50 to about 200 mg. The specific amount of thesecond active agent will depend on the specific agent used, the type ofdisease being treated or managed, the severity and stage of disease, andthe amount(s) of compounds provided herein and any optional additionalactive agents concurrently administered to the patient.

As discussed elsewhere herein, also encompassed is a method of reducing,treating and/or preventing adverse or undesired effects associated withconventional therapy including, but not limited to, surgery,chemotherapy, radiation therapy, hormonal therapy, biological therapyand immunotherapy. Compounds provided herein and other activeingredients can be administered to a patient prior to, during, or afterthe occurrence of the adverse effect associated with conventionaltherapy.

5.5 Cycling Therapy

In certain embodiments, the prophylactic or therapeutic agents providedherein are cyclically administered to a patient. Cycling therapyinvolves the administration of an active agent for a period of time,followed by a rest (i.e., discontinuation of the administration) for aperiod of time, and repeating this sequential administration. Cyclingtherapy can reduce the development of resistance to one or more of thetherapies, avoid or reduce the side effects of one of the therapies,and/or improve the efficacy of the treatment.

Consequently, in one embodiment, a compound provided herein isadministered daily in a single or divided doses in a four to six weekcycle with a rest period of about a week or two weeks. Cycling therapyfurther allows the frequency, number, and length of dosing cycles to beincreased. Thus, another embodiment encompasses the administration of acompound provided herein for more cycles than are typical when it isadministered alone. In yet another embodiment, a compound providedherein is administered for a greater number of cycles than wouldtypically cause dose-limiting toxicity in a patient to whom a secondactive ingredient is not also being administered.

In one embodiment, a compound provided herein is administered daily andcontinuously for three or four weeks at a dose of from about 0.1 mg toabout 500 mg per day, followed by a rest of one or two weeks. In otherembodiments, the dose can be from about 1 mg to about 300 mg, from about0.1 mg to about 150 mg, from about 1 mg to about 200 mg, from about 10mg to about 100 mg, from about 0.1 mg to about 50 mg, from about 1 mg toabout 50 mg, from about 10 mg to about 50 mg, from about 20 mg to about30 mg, or from about 1 mg to about 20 mg, followed by a rest.

In one embodiment, a compound provided herein and a second activeingredient are administered orally, with administration of the compoundprovided herein occurring 30 to 60 minutes prior to the second activeingredient, during a cycle of four to six weeks. In another embodiment,the combination of a compound provided herein and a second activeingredient is administered by intravenous infusion over about 90 minutesevery cycle.

Typically, the number of cycles during which the combination treatmentis administered to a patient will be from about one to about 24 cycles,from about two to about 16 cycles, or from about four to about threecycles.

5.6 Pharmaceutical Compositions and Dosage Forms

Pharmaceutical compositions can be used in the preparation ofindividual, single unit dosage forms. Pharmaceutical compositions anddosage forms provided herein comprise one or more solid forms comprisinga compound provided herein, or a pharmaceutically acceptable salt,solvate, stereoisomer, clathrate, or prodrug thereof. Pharmaceuticalcompositions and dosage forms can further comprise one or moreexcipients.

Pharmaceutical compositions and dosage forms provided herein can alsocomprise one or more additional active ingredients. Examples of optionalsecond, or additional, active ingredients are disclosed in Section 4.3,above.

Single unit dosage forms provided herein are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), topical (e.g., eye drops or other ophthalmicpreparations), transdermal or transcutaneous administration to apatient. Examples of dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; powders;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; eye drops or other ophthalmic preparations suitable fortopical administration; and sterile solids (e.g., crystalline oramorphous solids) that can be reconstituted to provide liquid dosageforms suitable for parenteral administration to a patient.

The composition, shape, and type of dosage forms will typically varydepending on their use. For example, a dosage form used in the acutetreatment of a disease may contain larger amounts of one or more of theactive ingredients it comprises than a dosage form used in the chronictreatment of the same disease. Similarly, a parenteral dosage form maycontain smaller amounts of one or more of the active ingredients itcomprises than an oral dosage form used to treat the same disease. Theseand other ways in which specific dosage forms are used will vary fromone another will be readily apparent to those skilled in the art. See,e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing,Easton Pa. (1990).

In one embodiment, pharmaceutical compositions and dosage forms compriseone or more excipients. Suitable excipients are well known to thoseskilled in the art of pharmacy, and non-limiting examples of suitableexcipients are provided herein. Whether a particular excipient issuitable for incorporation into a pharmaceutical composition or dosageform depends on a variety of factors well known in the art including,but not limited to, the way in which the dosage form will beadministered to a patient. For example, oral dosage forms such astablets may contain excipients not suited for use in parenteral dosageforms. The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients may be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines are particularly susceptibleto such accelerated decomposition. Consequently, provided arepharmaceutical compositions and dosage forms that contain little, ifany, lactose other mono- or di-saccharides. As used herein, the term“lactose-free”means that the amount of lactose present, if any, isinsufficient to substantially increase the degradation rate of an activeingredient.

Lactose-free compositions can comprise excipients that are well known inthe art and are listed, for example, in the U.S. Pharmacopeia (USP)25-NF20 (2002). In general, lactose-free compositions comprise activeingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. In one embodiment,lactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and magnesium stearate.

Also provided are anhydrous pharmaceutical compositions and dosage formscomprising active ingredients, since water can facilitate thedegradation of some compounds. For example, the addition of water (e.g.,5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long-term storage in order to determine characteristics suchas shelf-life or the stability of formulations over time. See, e.g.,Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed.,Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heataccelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms can be preparedusing anhydrous or low moisture containing ingredients and low moistureor low humidity conditions. Pharmaceutical compositions and dosage formsthat comprise lactose and at least one active ingredient that comprisesa primary or secondary amine are preferably anhydrous if substantialcontact with moisture and/or humidity during manufacturing, packaging,and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are, in one embodiment, packaged using materials known toprevent exposure to water such that they can be included in suitableformulary kits. Examples of suitable packaging include, but are notlimited to, hermetically sealed foils, plastics, unit dose containers(e.g., vials), blister packs, and strip packs.

Also provided are pharmaceutical compositions and dosage forms thatcomprise one or more compounds that reduce the rate by which an activeingredient will decompose. Such compounds, which are referred to hereinas “stabilizers,” include, but are not limited to, antioxidants such asascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. In one embodiment, dosage forms comprise a compoundprovided herein in an amount of from about 0.10 to about 500 mg. Inother embodiments, dosage forms comprise a compound provided herein inan amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50,100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.

In other embodiments, dosage forms comprise the second active ingredientin an amount of I to about 1000 mg, from about 5 to about 500 mg, fromabout 10 to about 350 mg, or from about 50 to about 200 mg. Of course,the specific amount of the second active agent will depend on thespecific agent used, the diseases or disorders being treated or managed,and the amount(s) of a compound provided herein, and any optionaladditional active agents concurrently administered to the patient.

5.6.1 Oral Dosage Forms

Pharmaceutical compositions that are suitable for oral administrationcan be provided as discrete dosage forms, such as, but not limited to,tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g.,flavored syrups). Such dosage forms contain predetermined amounts ofactive ingredients, and may be prepared by methods of pharmacy wellknown to those skilled in the art. See generally, Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).

Oral dosage forms provided herein are prepared by combining the activeingredients in an intimate admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

In one embodiment, oral dosage forms are tablets or capsules, in whichcase solid excipients are employed. In another embodiment, tablets canbe coated by standard aqueous or nonaqueous techniques. Such dosageforms can be prepared by any of the methods of pharmacy. In general,pharmaceutical compositions and dosage forms are prepared by uniformlyand intimately admixing the active ingredients with liquid carriers,finely divided solid carriers, or both, and then shaping the productinto the desired presentation if necessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms providedherein include, but are not limited to, binders, fillers, disintegrants,and lubricants. Binders suitable for use in pharmaceutical compositionsand dosage forms include, but are not limited to, corn starch, potatostarch, or other starches, gelatin, natural and synthetic gums such asacacia, sodium alginate, alginic acid, other alginates, powderedtragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodiumcarboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose,pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Anspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms provided herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions is, in oneembodiment, present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants may be used in the compositions to provide tablets thatdisintegrate when exposed to an aqueous environment. Tablets thatcontain too much disintegrant may disintegrate in storage, while thosethat contain too little may not disintegrate at a desired rate or underthe desired conditions. Thus, a sufficient amount of disintegrant thatis neither too much nor too little to detrimentally alter the release ofthe active ingredients may be used to form solid oral dosage forms. Theamount of disintegrant used varies based upon the type of formulation,and is readily discernible to those of ordinary skill in the art. In oneembodiment, pharmaceutical compositions comprise from about 0.5 to about15 weight percent of disintegrant, or from about 1 to about 5 weightpercent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, agar-agar, alginic acid, calciumcarbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, potato ortapioca starch, other starches, pre-gelatinized starch, other starches,clays, other algins, other celluloses, gums, and mixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, calcium stearate, magnesiumstearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zincstearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.Additional lubricants include, for example, a syloid silica gel(AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, Md.), acoagulated aerosol of synthetic silica (marketed by Degussa Co. ofPiano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants may be used in an amount of less than about 1 weight percentof the pharmaceutical compositions or dosage forms into which they areincorporated.

In one embodiment, a solid oral dosage form comprises a compoundprovided herein, anhydrous lactose, microcrystalline cellulose,polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, andgelatin.

5.6.2 Controlled Release Dosage Forms

Active ingredients provided herein can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active agents provided herein. In one embodiment, provided aresingle unit dosage forms suitable for oral administration such as, butnot limited to, tablets, capsules, gelcaps, and caplets that are adaptedfor controlled-release.

In one embodiment, controlled-release pharmaceutical products improvedrug therapy over that achieved by their non-controlled counterparts. Inanother embodiment, the use of a controlled-release preparation inmedical treatment is characterized by a minimum of drug substance beingemployed to cure or control the condition in a minimum amount of time.Advantages of controlled-release formulations include extended activityof the drug, reduced dosage frequency, and increased patient compliance.In addition, controlled-release formulations can be used to affect thetime of onset of action or other characteristics, such as blood levelsof the drug, and can thus affect the occurrence of side (e.g., adverse)effects.

In another embodiment, the controlled-release formulations are designedto initially release an amount of drug (active ingredient) that promptlyproduces the desired therapeutic or prophylactic effect, and graduallyand continually release of other amounts of drug to maintain this levelof therapeutic or prophylactic effect over an extended period of time.In one embodiment, in order to maintain a constant level of drug in thebody, the drug can be released from the dosage form at a rate that willreplace the amount of drug being metabolized and excreted from the body.Controlled-release of an active ingredient can be stimulated by variousconditions including, but not limited to, pH, temperature, enzymes,water, or other physiological conditions or compounds.

5.6.3 Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. In someembodiments, administration of a parenteral dosage form bypassespatients' natural defenses against contaminants, and thus, in theseembodiments, parenteral dosage forms are sterile or capable of beingsterilized prior to administration to a patient. Examples of parenteraldosage forms include, but are not limited to, solutions ready forinjection, dry products ready to be dissolved or suspended in apharmaceutically acceptable vehicle for injection, suspensions ready forinjection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage formsare well known to those skilled in the art. Examples include, but arenot limited to: Water for Injection USP; aqueous vehicles such as, butnot limited to, Sodium Chloride Injection, Ringer's Injection, DextroseInjection, Dextrose and Sodium Chloride Injection, and Lactated Ringer'sInjection; water-miscible vehicles such as, but not limited to, ethylalcohol, polyethylene glycol, and polypropylene glycol; and non-aqueousvehicles such as, but not limited to, corn oil, cottonseed oil, peanutoil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms. For example, cyclodextrin and its derivativescan be used to increase the solubility of a compound provided herein.See e.g., U.S. Pat. No. 5,134,127, which is incorporated herein byreference.

5.6.4 Topical and Mucosal Dosage Forms

Topical and mucosal dosage forms provided herein include, but are notlimited to, sprays, aerosols, solutions, emulsions, suspensions, eyedrops or other ophthalmic preparations, or other forms known to one ofskill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16thand 18th eds., Mack Publishing, Easton Pa. (1980 & 1990); andIntroduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger,Philadelphia (1985). Dosage forms suitable for treating mucosal tissueswithin the oral cavity can be formulated as mouthwashes or as oral gels.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide topical and mucosal dosage forms encompassedherein are well known to those skilled in the pharmaceutical arts, anddepend on the particular tissue to which a given pharmaceuticalcomposition or dosage form will be applied. In one embodiment,excipients include, but are not limited to, water, acetone, ethanol,ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,isopropyl palmitate, mineral oil, and mixtures thereof to formsolutions, emulsions or gels, which are non-toxic and pharmaceuticallyacceptable. Moisturizers or humectants can also be added topharmaceutical compositions and dosage forms. Examples of additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990).

The pH of a pharmaceutical composition or dosage form may also beadjusted to improve delivery of one or more active ingredients. Also,the polarity of a solvent carrier, its ionic strength, or tonicity canbe adjusted to improve delivery. Compounds such as stearates can also beadded to pharmaceutical compositions or dosage forms to alter thehydrophilicity or lipophilicity of one or more active ingredients so asto improve delivery. In other embodiments, stearates can serve as alipid vehicle for the formulation, as an emulsifying agent orsurfactant, or as a delivery-enhancing or penetration-enhancing agent.In other embodiments, salts, solvates, prodrugs, clathrates, orstereoisomers of the active ingredients can be used to further adjustthe properties of the resulting composition.

5.7 Kits

In one embodiment, active ingredients provided herein are notadministered to a patient at the same time or by the same route ofadministration. In another embodiment, provided are kits which cansimplify the administration of appropriate amounts of activeingredients.

In one embodiment, a kit comprises a dosage form of a compound providedherein. Kits can further comprise additional active ingredients such asoblimersen (Genasense®), melphalan, G-CSF, GM-CSF, EPO, topotecan,dacarbazine, irinotecan, taxotere, IFN, COX-2 inhibitor, pentoxifylline,ciprofloxacin, dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine,isotretinoin, 13 cis-retinoic acid, or a pharmacologically active mutantor derivative thereof, or a combination thereof. Examples of theadditional active ingredients include, but are not limited to, thosedisclosed herein (see, e.g., section 4.3).

In other embodiments, kits can further comprise devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, drip bags, patches, and inhalers.

Kits can further comprise cells or blood for transplantation as well aspharmaceutically acceptable vehicles that can be used to administer oneor more active ingredients. For example, if an active ingredient isprovided in a solid form that must be reconstituted for parenteraladministration, the kit can comprise a sealed container of a suitablevehicle in which the active ingredient can be dissolved to form aparticulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

6. EXAMPLES

Certain embodiments provided herein are illustrated by the followingnon-limiting examples.

6.1 3-(2,5-Dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione

A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-methyl-benzamide(1.00 g, 3.8 mmol) and triethyl orthoacetate (0.9 mL, 4.9 mmol) in DMF(10 mL) was heated to reflux for 1 hour. The mixture was cooled to roomtemperature. To the solution, Celite (40 mL) was added, and the solventwas removed in vacuo. The solid was loaded on a SIM and purified withISCO flash gel chromatography (silica gel, CH₃OH/CH₂Cl₂) to give3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as anoff-white solid (0.46 g, 43% yield): HPLC: Waters Symmetry C₁₋₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 25/75 CH₃CN/0.1% H₃PO₄, 2.95 min (96%);mp: 292-294° C.; ¹H NMR (DMSO-d₆) δ 2.11-2.18 (m, 1H, CHH), 2.55-2.65(m, 2H, CH₂), 2.60 (s, 3H, CH₃), 2.69 (s, 3H, CH₃), 2.78-2.85 (m, 1H;CHH), 5.19 (dd, J=6, 11 Hz, 1H, NCh), 7.25 (d, J=8 Hz, 1H, Ar), 7.43 (d,J=8 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 10.99 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 20.82, 22.43, 23.32, 30.55, 56.33, 118.69, 124.73, 128.82,133.72, 139.82, 148.34, 154.58, 161.03, 169.61, 172.60; LCMS: MH=286;Anal. Calcd. for C₁₅H₁₅N₃O₃+1H₂O: C, 59.26; H, 5.68; N, 13.66. Found: C,59.26; H, 5.68; N, 13.66.

6.2 Preparation and Characterization of Solid Forms of3-(2,5-Dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione 6.2.1Form A of 3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione6.2.1.1 Crystallization

Form A was prepared via crystallization of3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione inseveral organic solvent systems. Slurry crystallizations were performedby adding an excess of solid3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione to 2 mlof the desired solvent system, then agitating the resulting mixture fora minimum of 24 hours at a controlled temperature. Upon reachingequilibrium, the solids were filtered, air-dried and characterized. FormA was prepared by slurry crystallization of Form B in each of thefollowing solvents at 25° C.: acetone; acetonitrile; n-butanol; ethanol;methanol; methyl ethyl ketone; 2-propanol; and tetrahydrofuran.

Form A was stable when slurried in any of the following solvents at 25°C.: acetone; acetonitrile; n-butanol; ethanol; ethyl acetate; heptane;methanol; methylene chloride; methyl ethyl ketone; methyl t-butyl ether;2-propanol; toluene; and tetrahydrofuran. Form A was stable whenslurried in any of the following solvents at 50° C.: acetone;acetonitrile; n-butanol; ethanol; ethyl acetate; heptane; methanol;methyl ethyl ketone; methyl t-butyl ether; 2-propanol; toluene; andtetrahydrofuran.

6.2.1.2 Solubility

The solubility of Form A was investigated in a number of solvents atambient conditions. Solubility measurements were obtained by addingsolvent (either HPLC grade or reagent grade) to a carefully weighed(approximately 100 mg) sample of Form A. The resulting mixture wasagitated for at least 24 hours at 25° C. The solubility was estimatedbased on the total volume of solvent required to give a completesolution. In addition, a known volume of filtrate was evaporated todryness and the weight of the residue was measured. The measuredsolubility of Form in a variety of solvents is presented in Table 1.

TABLE 1 Approximate Measured Solubility of Form A and Form B of 3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione Form AApproximate Form B Approximate Solvent Solubility (mg/ml) Solubility(mg/ml) Acetone 2.07 2.56 Acetonitrile 1.49 1.40 n-Butanol 0.23 0.34Absolute ethanol 0.50 0.50 Ethyl acetate 0.67 1.16 Heptane 0.43 0.44Methylene chloride 2.12 1.63 Methyl ethyl ketone 1.39 1.57 Methanol 1.281.31 Methyl t-butyl ether 0.42 0.43 2-Propanol 0.21 0.35 Tetrahydrofuran4.57 4.71 Toluene 0.32 0.20 Water 0.17 0.10 Ethanol/Water (1/1) 0.180.28

6.2.1.3 Stability

The stability of Form A was investigated by exposing a sample of Form Ato a 40° C./75% RH environment for four weeks. The Form A sample wassubstantially unchanged under these conditions, as indicated by X-raypowder diffraction.

The stability of Form A was further investigated by storing a slurry ofForm A in each of the following solvents at 40° C. for four weeks:acetone; acetonitrile; ethanol; heptane; 2-propanol; methyl t-butylether; methanol; water; and ethanol/water (1/1). The Form A material wasstable in acetone; acetonitrile; ethanol; heptane; 2-propanol; methylt-butyl ether; and methanol. In water and ethanol/water, the Form Amaterial converted into the Form B crystal form.

The stability of Form A was further investigated using compressiontesting. Compression testing of Form A was carried out by applying 2,000psi pressure to a sample of Form A for approximately 1 minute, followedby analysis for stability using X-ray powder diffraction. Compressiontesting on Form A revealed that Form A is substantially unchanged aftercompression.

6.2.1.4 Moisture Sorption

The moisture sorption/desorption behavior of Form A was investigated byDynamic Vapor Sorption (DVS). Form A exhibited a 0.7% mass changerelative to the dry mass when the relative humidity (RH) was increasedfrom 0% to 95% RH. At the end of the desorption cycle, the sample lostall of the weight it had gained during the process of moisture sorption.After completion of the adsorption/desorption cycle, the XRPDdiffractogram of the sample showed that the material was substantiallyunchanged from the initial Form A.

6.2.2 Form B of3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione 6.2.2.1Crystallization

Form B was prepared via crystallization of3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione inseveral organic and aqueous solvent systems, includingdimethylsulfoxide/water. Slurry crystallizations were performed byadding an excess of solid3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione to 2 mlof the desired solvent system, then agitating the resulting mixture fora minimum of 24 hours at a controlled temperature. Upon reachingequilibrium, the solids were filtered, air-dried and characterized. FormB was prepared by slurry crystallization of Form A in the followingsolvents at both 25° C. and 50° C.: water; and ethanol/water (1/1).

Form B was stable when slurried in the following solvents at 25° C.:ethyl acetate; heptane; methylene chloride; methyl t-butyl ether;toluene; water; and ethanol/water (1/1).

6.2.2.2 Solubility

The solubility of Form B was investigated in a number of solvents atambient conditions. Solubility measurements were obtained by addingsolvent (either HPLC grade or reagent grade) to a carefully weighed(approximately 100 mg) sample of Form B. The resulting mixture wasagitated for at least 24 hours at 25° C. The solubility was estimatedbased on the total volume of solvent required to give a completesolution. In addition, a known volume of filtrate was evaporated todryness and the weight of the residue was measured. The measuredsolubility of Form in a variety of solvents is presented in Table 1.

6.2.2.3 Stability

The stability of Form B was investigated by exposing a sample of Form Bto a 40° C./75% RH environment for four weeks. The Form B sample wassubstantially unchanged under these conditions, as indicated by X-raypowder diffraction.

The stability of Form B was further investigated by storing a slurry ofForm B in the following solvents at 40° C. for four weeks: acetone;acetonitrile; ethanol; heptane; 2-propanol; methyl t-butyl ether;methanol; water; and ethanol/water (1/1). The Form B material was stablein heptane; methyl t-butyl ether; water; and ethanol/water (1/1). Inacetone, acetonitrile, ethanol and methanol the Form B materialconverted into the Form A crystal form. In 2-propanol, the Form Bmaterial converted to a mixture of Forms A and B.

The stability of Form B was further investigated using compressiontesting. Compression testing of Form B was carried out by applying 2,000psi pressure to a sample of Form B for approximately 1 minute, followedby analysis for stability using X-ray powder diffraction. Compressiontesting on Form B revealed that Form B is substantially unchanged aftercompression.

6.2.2.4 Moisture Sorption

The moisture sorption/desorption behavior of Form B was investigated byDynamic Vapor Sorption (DVS). Form B exhibited a 2.9% mass changerelative to the dry mass when the relative humidity (RH) was increasedfrom 0% to 95% RH. At the end of the desorption cycle, the sample lostall of the weight it had gained during the process of moisture sorption.After completion of the adsorption/desorption cycle, the XRPDdiffractogram of the sample showed that the material was substantiallyunchanged from the initial Form B.

6.2.3 General Characterization Methods

X-ray powder diffraction (XRPD) analysis was conducted using a ThermoARL X'TRA X-ray powder diffractometer using CuKα radiation at 1.54 Å.The instrument was equipped with a fine focus X-ray tube. The voltageand amperage of the X-ray generator were set at 45 kV and 40 mA, and themeasuring slits were set at 0.5 mm and 0.2 mm. Diffracted radiation wasmeasured using a Peltier-cooled Si (Li) solid-state detector. Atheta-two theta continuous scan at 2.40°/min (0.5 sec/0.02° step) from1.5°2θ to 40°2θ was used. A sintered alumina standard was used as areference.

Differential Scanning Calorimetry (DSC) analyses were performed on a TAInstruments Q1000 Differential Scanning Caolorimeter. Indium was used asa calibration standard. Approximately 2-5 mg of sample was placed into aDSC pan and the weight was accurately recorded. The sample was heatedunder nitrogen at a rate of 10° C./min from ambient temperature up to afinal temperature of 300° C. Melting points were reported as theextrapolated onset temperatures.

Thermogravimetric (TG) analyses were performed on a TA Instruments Q500Thermogravimetric Analyzer. A calcium oxalate standard was used as areference. Approximately 10-25 mg of accurately weighed sample wasplaced on a pan and loaded into the TG furnace. The sample was heatedunder nitrogen at a rate of 10° C./min from ambient temperature up to afinal temperature of 300° C.

Morphology analysis of the samples was performed using an Olympusmicroscope. The instrument was calibrated using USP standards.

Hygroscopicity was determined using a Surface Measurement Systems DVSinstrument. Typically, a sample size of 10-50 mg was loaded into the DVSinstrument sample pan and the sample was analyzed on a DVS automatedsorption analyzer at 25° C. The relative humidity (RH) was increasedfrom 0% RH to 95% RH. The RH was then decreased in a similar manner toaccomplish a full adsorption/desorption cycle.

The general characterization methods described herein are non-limiting,and are intended merely as examples of parameters, methods andtechniques which can be used to analyze certain embodiments providedherein. Other standard parameters, methods and techniques for chemical,biological, physiological and solid-state analysis are contemplatedherein as means of characterizing various embodiments provided herein.

6.3 Assays 6.3.1 TNFα Inhibition Assay in PMBC

Peripheral blood mononuclear cells (PBMC) from normal donors areobtained by Ficoll Hypaque (Pharmacia, Piscataway, N.J., USA) densitycentrifugation. Cells are cultured in RPMI 1640 (Life Technologies,Grand Island, N.Y., USA) supplemented with 10% AB+human serum (GeminiBio-products, Woodland, Calif., USA), 2 mM L-glutamine, 100 U/mlpenicillin, and 100 μg/ml streptomycin (Life Technologies).

PBMC (2×10⁵ cells) are plated in 96-well flat-bottom Costar tissueculture plates (Corning, N.Y., USA) in triplicate. Cells are stimulatedwith LPS (from Salmonella abortus equi, Sigma cat.no. L-1887, St. Louis,Mo., USA) at 1 ng/ml final in the absence or presence of compounds.Compounds provided herein are dissolved in DMSO (Sigma) and furtherdilutions are done in culture medium immediately before use. The finalDMSO concentration in all assays can be about 0.25%. Compounds are addedto cells 1 hour before LPS stimulation. Cells are then incubated for18-20 hours at 37° C. in 5% CO₂, and supernatants are then collected,diluted with culture medium and assayed for TNFα levels by ELISA(Endogen, Boston, Mass., USA). IC₅₀s are calculated using non-linearregression, sigmoidal dose-response, constraining the top to 100% andbottom to 0%, allowing variable slope (GraphPad Prism v3.02).

6.3.2 IL-2 and MIP-3a Production by T Cells

PBMC are depleted of adherent monocytes by placing 1×10⁸ PBMC in 10 mlcomplete medium (RPMI 1640 supplemented with 10% heat-inactivated fetalbovine serum, 2 mM L-glutamine, 100 U/ml penicillin, and 100 μg/mlstreptomycin) per 10 cm tissue culture dish, in 37° C., 5% CO₂ incubatorfor 30-60 minutes. The dish is rinsed with medium to remove allnon-adherent PBMC. T cells are purified by negative selection using thefollowing antibody (Pharmingen) and Dynabead (Dynal) mixture for every1×10⁸ non-adherent PBMC: 0.3 ml Sheep anti-mouse IgG beads, 15 μlanti-CD16, 15 μl anti-CD33, 15 μl anti-CD56, 0.23 ml anti-CD19 beads,0.23 ml anti-HLA class II beads, and 56 μl anti-CD14 beads. The cellsand bead/antibody mixture is rotated end-over-end for 30-60 minutes at4° C. Purified T cells are removed from beads using a Dynal magnet.Typical yield is about 50% T cells, 87-95% CD3+ by flow cytometry.

Tissue culture 96-well flat-bottom plates are coated with anti-CD3antibody OKT3 at 5 μg/ml in PBS, 100 μl per well, incubated at 37° C.for 3-6 hours, then washed four times with complete medium 100 μl/welljust before T cells are added. Compounds are diluted to 20 times offinal in a round bottom tissue culture 96-well plate. Finalconcentrations are about 10 μM to about 0.00064 μM. A 10 mM stock ofcompounds provided herein is diluted 1:50 in complete for the first 20×dilution of 200 μM in 2% DMSO and serially diluted 1:5 into 2% DMSO.Compound is added at 10 μl per 200 μl culture, to give a final DMSOconcentration of 0.1%. Cultures are incubated at 37° C., 5% CO₂ for 2-3days, and supernatants analyzed for IL-2 and MIP-3α by ELISA (R&DSystems). IL-2 and MIP-3u levels are normalized to the amount producedin the presence of an amount of a compound provided herein, and EC₅₀scalculated using non-linear regression, sigmoidal dose-response,constraining the top to 100% and bottom to 0%, allowing variable slope(GraphPad Prism v3.02).

6.3.3 Cell Proliferation Assay

Cell lines Namalwa, MUTZ-5, and UT-7 are obtained from the DeutscheSammlung von Mikroorganismen und Zellkulturen GmbH (Braunschweig,Germany). The cell line KG-1 is obtained from the American Type CultureCollection (Manassas, Va., USA). Cell proliferation as indicated by³H-thymidine incorporation is measured in all cell lines as follows.

Cells are plated in 96-well plates at 6000 cells per well in media. Thecells are pre-treated with compounds at about 100, 10, 1, 0.1, 0.01,0.001, 0.0001 and 0 μM in a final concentration of about 0.25% DMSO intriplicate at 37° C. in a humidified incubator at 5% CO₂ for 72 hours.One microcurie of ³H-thymidine (Amersham) is then added to each well,and cells are incubated again at 37° C. in a humidified incubator at 5%CO₂ for 6 hours. The cells are harvested onto UniFilter GF/C filterplates (Perkin Elmer) using a cell harvester (Tomtec), and the platesare allowed to dry overnight. Microscint 20 (Packard) (25 μl/well) isadded, and plates are analyzed in TopCount NXT (Packard). Each well iscounted for one minute. Percent inhibition of cell proliferation iscalculated by averaging all triplicates and normalizing to the DMSOcontrol (0% inhibition). Each compound is tested in each cell line inthree separate experiments. Final IC₅₀s are calculated using non-linearregression, sigmoidal dose-response, constraining the top to 100% andbottom to 0%, allowing variable slope. (GraphPad Prism v3.02).

6.3.4 Immunoprecipitation and Immunoblot

Namalwa cells are treated with DMSO or an amount of a compound providedherein for 1 hour, then stimulated with 10 U/ml of Epo (R&D Systems) for30 minutes. Cell lysates are prepared and either immunoprecipitated withEpo receptor Ab or separated immediately by SDS-PAGE. Immunoblots areprobed with Akt, phospho-Akt (Ser473 or Thr308), phospho-Gab1 (Y627),Gab1, IRS2, actin and IRF-1 Abs and analyzed on a Storm 860 Imager usingImageQuant software (Molecular Dynamics).

6.3.5 Cell Cycle Analysis

Cells are treated with DMSO or an amount of a compound provided hereinovernight. Propidium iodide staining for cell cycle is performed usingCycleTEST PLUS (Becton Dickinson) according to manufacturer's protocol.Following staining, cells are analyzed by a FACSCalibur flow cytometerusing ModFit LT software (Becton Dickinson).

6.3.6 Apoptosis Analysis

Cells are treated with DMSO or an amount of a compound provided hereinat various time points, then washed with annexin-V wash buffer (BDBiosciences). Cells are incubated with annexin-V binding protein andpropidium iodide (BD Biosciences) for 10 minutes. Samples are analyzedusing flow cytometry.

6.3.7 Luciferase Assay

Namalwa cells are transfected with 4 μg of API-luciferase (Stratagene)per 1×10⁶ cells and 3 μl Lipofectamine 2000 (Invitrogen) reagentaccording to manufacturer's instructions. Six hours post-transfection,cells are treated with DMSO or an amount of a compound provided herein.Luciferase activity is assayed using luciferase lysis buffer andsubstrate (Promega) and measured using a luminometer (Turner Designs).

The embodiments described above are intended to be merely exemplary, andthose skilled in the art will recognize, or will be able to ascertainusing no more than routine experimentation, numerous equivalents ofspecific compounds, materials, and procedures. All such equivalents areconsidered to be within the scope of the invention and are encompassedby the appended claims.

All of the patents, patent applications and publications referred toherein are incorporated herein in their entireties. Citation oridentification of any reference in this application is not an admissionthat such reference is available as prior art. The full scope of theinvention is better understood with reference to the appended claims.

1. Crystalline Form A of3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dioneexhibiting an X-ray powder diffraction pattern comprising peaks atapproximately 13.7°2θ, 21.8°2θ and 27.5°2θ when analyzed using CuKαX-ray radiation.
 2. The crystal form of claim 1 exhibiting an X-raypowder diffraction further comprising peaks at approximately 9.8°2θ,17.4°2θ and 26.3°2θ.
 3. The crystal form of claim 1 exhibiting an X-raypowder diffraction pattern comprising peaks at approximately 9.8°2θ,12.1°2θ, 13.7°2θ, 15.1°2θ, 17.4°2θ, 21.5°2θ, 21.8°2θ, 26.3°2θ, 27.5°2θ,and 32.5°2θ.
 4. The crystal form of claim 1 exhibiting athermogravimetric analysis thermogram comprising a total mass loss ofless than approximately 1% of the total mass of the sample between thetemperatures of approximately 25° C. and approximately 220° C.
 5. Thecrystal form of claim 1 exhibiting a differential scanning calorimetrythermogram comprising an endothermic event with an onset temperature ofapproximately 292° C. when heated from approximately 25° C. toapproximately 300° C.
 6. The crystal form of claim 1 exhibiting amoisture sorption isotherm comprising a total mass increase ofapproximately 1% of the total mass of the sample when the humidity isincreased from approximately 0% RH to approximately 50% RH at a constanttemperature of approximately 23° C.
 7. The crystal form of claim 1exhibiting a moisture sorption isotherm comprising a total mass increaseof approximately 4% of the total mass of the sample when the humidity isincreased from approximately 0% RH to approximately 95% RH at a constanttemperature of approximately 23° C.
 8. The crystal form of claim 1 whichis substantially chemically pure.
 9. The crystal form of claim 1 whichis substantially free of solvent and water in the crystal lattice. 10.Crystalline Form B of3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dioneexhibiting an X-ray powder diffraction pattern comprising peaks atapproximately 9.1°2θ, 14.1°2θ and 21.1°2θ when analyzed using CuKα X-rayradiation.
 11. The crystal form of claim 10 which contains approximately1 molar equivalent of water in the crystal lattice per mole of3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione.
 12. Thecrystal form of claim 10 exhibiting an X-ray powder diffraction patternfurther comprising peaks at approximately 15.1°2θ and 16.6°2θ.
 13. Thecrystal form of claim 10 exhibiting an X-ray powder diffraction patterncomprising peaks at approximately 9.1°2θ, 14.1°2θ, 15.1°2θ, 16.6°2θ,21.1°2θ, 21.8°2θ, 25.1°2θ, 28.7°2θ, and 35.4°2θ.
 14. The crystal form ofclaim 10 exhibiting a thermogravimetric analysis thermogram comprising atotal mass loss of approximately 6% of the total mass of the samplebetween the temperatures of approximately 25° C. and approximately 150°C.
 15. The crystal form of claim 10 exhibiting a differential scanningcalorimetry thermogram comprising an endothermic event with a peaktemperature of approximately 139° C. when heated from approximately 25°C. to approximately 300° C.
 16. The crystal form of claim 15 exhibitinga differential scanning calorimetry thermogram further comprising anendothermic event with an onset temperature of approximately 290° C. 17.The crystal form of claim 10 exhibiting a moisture sorption isothermcomprising a total mass increase of approximately 1.5% of the total massof the sample when the humidity is increased from approximately 0% RH toapproximately 50% RH at a constant temperature of approximately 23° C.18. The crystal form of claim 10 exhibiting a moisture sorption isothermcomprising a total mass increase of approximately 3% of the total massof the sample when the humidity is increased from approximately 0% RH toapproximately 95% RH at a constant temperature of approximately 23° C.19. The crystal form of claim 10 which is substantially chemically pure.20. A pharmaceutical composition comprising the crystal form of claim 1or 10.